As Helicobacter pylori is a first-class carcinogen, eradication of the infection would be expected to be a beneficial measure for the (primary) prevention of gastric cancer. Given the natural history of gastric cancer, it is plausible that eradication before gastric atrophy sets in offers the best chance for cancer risk reduction. The beneficial effects of eradication may, nevertheless, still be achievable in more advanced disease. The reversibility of inflammatory lesions has been supported by undeniable evidence; the regression of mucosal atrophy/metaplasia has also been confirmed by several recent histologic studies.
Key points
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Helicobacter pylori is a first-class carcinogen; the eradication of the infection is a primary cancer-prevention strategy.
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In gastric mucosa, H pylori infection results in both (1) inflammation (ie, gastritis) and (2) structural modifications of the native anatomy/function (ie, precancerous lesions: atrophy/metaplasia, intraepithelial neoplasia [synonym dysplasia]).
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Anatomic changes are assessable by endoscopy/biopsy. Pepsinogen serology mirrors gastric mucosa atrophy with a high negative predictive value.
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Following H pylori eradication, the rate of reversion of the histology lesions decreases along with their increasing severity.
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Successful eradication invariably results in eliminating the H pylori –associated mucosal inflammation (ie, the inflammatory component of the mucosal damage).
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Mucosal atrophy and intestinal metaplasia may (at least partially) be reversed by H pylori eradication (the higher the gastritis stage, the lower/slower the reversion rate).
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Contradictory information is available on the benefit achievable by eradicating patients with advanced precancerous lesions (ie, intraepithelial neoplasia); beneficial effects have been reported only in association with low-grade lesions.
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In patients (endoscopically/surgically) treated for early gastric cancer, H pylori eradication delays/lowers the risk of metachronous cancers.
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The choice of eradicating is independent from both the severity of the mucosal damage and the (expected) rate of its reversibility; the mucosal status at eradication time only affects the timing/strategy of posteradication interventions (follow-up, ablation, surgical therapy).
Introduction
The so-called epidemic or intestinal-type gastric cancer (GC) is the most frequent gastric neoplasia, and the fact that its (race-independent) incidence is declining throughout all developed countries supports the hypothesis that environmental factors play a major role in its cause. A second clinico-biological variant of GC is hereditary (ie, syndromic), and it is associated with specific mutational profiles; the epidemiologic impact of this variant is negligible.
Irrespective of its morphologic/epidemiologic variants, GC is associated with a poor prognosis, with a 5-year overall survival rate lower than 30%.
The onset of intestinal-type GC is definitively associated with age (older than 50 years), which is consistent with the most accepted theory concerning the long natural history of GC. Chronic gastritis (mostly caused by H pylori infection) may represent the earliest phase of gastric oncogenesis. After several decades, long-standing inflammation extensively modifies the native gastric mucosa, creating a microenvironment prone to cancer development. This “cancerization field” consists of 2 main types of lesions: (1) inflammation of the gastric mucosa and (2) gastric mucosal atrophy characterized by both an absolute loss of resident glandular units and/or a metaplastic transformation (eg, intestinalization) of native glandular structures. The metaplastic epithelium may further undergo dedifferentiation, acquiring most of the biological characteristics of neoplastic cells but still lacking invasion capability (intraepithelial neoplasia [IEN], formerly defined as dysplasia). By acquiring stromal invasion capability, IEN ultimately progresses to invasive cancer.
GC’s natural history, known as Correa oncogenic cascade, provides a biological rationale behind the multidisciplinary approach for primary and secondary prevention strategies.
Introduction
The so-called epidemic or intestinal-type gastric cancer (GC) is the most frequent gastric neoplasia, and the fact that its (race-independent) incidence is declining throughout all developed countries supports the hypothesis that environmental factors play a major role in its cause. A second clinico-biological variant of GC is hereditary (ie, syndromic), and it is associated with specific mutational profiles; the epidemiologic impact of this variant is negligible.
Irrespective of its morphologic/epidemiologic variants, GC is associated with a poor prognosis, with a 5-year overall survival rate lower than 30%.
The onset of intestinal-type GC is definitively associated with age (older than 50 years), which is consistent with the most accepted theory concerning the long natural history of GC. Chronic gastritis (mostly caused by H pylori infection) may represent the earliest phase of gastric oncogenesis. After several decades, long-standing inflammation extensively modifies the native gastric mucosa, creating a microenvironment prone to cancer development. This “cancerization field” consists of 2 main types of lesions: (1) inflammation of the gastric mucosa and (2) gastric mucosal atrophy characterized by both an absolute loss of resident glandular units and/or a metaplastic transformation (eg, intestinalization) of native glandular structures. The metaplastic epithelium may further undergo dedifferentiation, acquiring most of the biological characteristics of neoplastic cells but still lacking invasion capability (intraepithelial neoplasia [IEN], formerly defined as dysplasia). By acquiring stromal invasion capability, IEN ultimately progresses to invasive cancer.
GC’s natural history, known as Correa oncogenic cascade, provides a biological rationale behind the multidisciplinary approach for primary and secondary prevention strategies.
Helicobacter pylori infection is the most important determinant of gastric cancer risk
As with most neoplastic diseases, GC is a multifactorial neoplasia. In most cases, environmental factors are the main cancer-promoting agents, but even in nonsyndromic (ie, sporadic) cancers, host-related factors are involved in cancer promotion.
Among all possible environmental factors, H pylori is consistently recognized as the leading etiologic agent of GC. In 1994, H pylori was recognized as a type I carcinogen; it is currently considered the most common etiologic agent linked to infection-related cancers, which represent 5.5% of the global cancer burden. Fig. 1 outlines the most relevant etio-pathogenetic factors involved in sporadic GCs.
Globally, about 3.5 billion people have the H pylori infection, and solid evidence supports a fecal-oral and/or gastric-oral transmission pattern that takes place early in life. The rates of H pylori infection vary considerably by geographic area, with a generally higher prevalence in developing countries. A large percentage of those who are infected develop non–self-limiting gastric inflammation; approximately 10% develop peptic (duodenal or gastric) ulcers; 3% develop gastric adenocarcinoma, with less than 0.5% developing mucosa-associated lymphoid tissue lymphoma.
The variable outcome of the infection probably depends on the infection’s bacterial properties, on environmental cofactors, as well as on host-related immune response modulation. All these variables must be taken into consideration when GC risk following H pylori eradication is being assessed.
Gastric cancer risk: epidemiologic trends
In highly developed countries, survival curves of patients with GC have consistently demonstrated a continuous decline in cancer-related mortality ( Fig. 2 ). This trend is, however, only partially explained by the advent of more efficient therapies; more realistically it seems to be the consequence of a declining cancer burden. In this epidemiologic setting, both GC and H pylori infection show the same declining incidence pattern. These two consistent patterns constitute a solid rationale for assuming that eradication of H pylori is an appropriate strategy for the primary prevention of GC.
Vaccinations constitute the ideal primary prevention against any infectious disease, but no vaccines are as yet available to prevent H pylori infection. Although primary intervention strategies basically rely on efforts to eradicate the bacteria, the best approach to eradication therapy has been, and continues to be, under debate (also in view of the emergence of antibiotic-resistant H pylori strains).
Gastric cancer risk: the assessment
GC risk can be assessed using both noninvasive and invasive methods.
Noninvasive approaches include assessment of demographic variables (age, sex, and ethnicity), subjective symptoms (clinical history and current symptoms), and laboratory findings (serology).
Invasive procedures include endoscopy and histology evaluation, which are 2 faces of the same coin: both are expensive and require a high level of technical expertise and a well-organized health care system.
Demographics
Nonsyndromic malignancies are associated with an age-related increased risk. With regard to GC, patients’ age also reflects the time between when the person was infected and the onset of the organic lesions (ie, extensive mucosal atrophy) in which intestinal-type GC most frequently develops.
In all ethnic groups, solid epidemiologic data link GC to the male sex. As it has been supported by reports confirming significant differences in GC incidence in various ethnic groups living in the same country, ethnicity per se seems to be a risk factor. Age-adjusted incidence rates of GC were found to vary between 29.3 per 100,00 and 3.4 per 100,000, respectively, in Chinese and Malaysian males, both living in Singapore. Even larger, significant differences were found between Korean and Filipino populations living in Los Angeles (35.5 vs 6.8, respectively). The available studies on the effect of ethnicity, however, mostly disregard the differences in the incidence of H pylori infection (Chinese vs Malays), the virulence of the infecting strains, and the diet (eg, Korans and Filipino populations in Los Angeles). The relationships between GC risk and dietary constituents (salt and nitrites as causal agents and fruits and vegetables as protective ones), lifestyle, and, more in general, socioeconomic status need to be further addressed and more exactly quantified.
Noninvasive Methods
The noninvasive assessment of GC risk basically relies on the well-established assumption that the risk of cancer parallels the incidence of atrophic gastritis; the latter can be reliably assessed by functionally testing the status of the gastric mucosa with serum pepsinogens, currently considered the best indicators of gastric atrophy. Pepsinogens (pepsinogen I [PgI] and pepsinogen II [PgII], in particular) are aspartic proteinases produced by gastric epithelia and secreted into the gastric lumen, where they are transformed into pepsin. PgI is produced in the chief cells of the oxyntic mucosa, whereas PgII is produced in both corpus and antral stomach mucosa. Any decrease in the oxyntic gland population (ie, corpus atrophy) leads to a reduction in the serum levels of PgI resulting in a lower PgI/PgII ratio. Pepsinogen testing was implemented long before H pylori was discovered and was rediscovered as a marker of GC risk (but not of GC itself).
In a large cohort of 22,000 Finnish subjects, the sensitivity and specificity for PgI/PgII value for the detection of atrophic gastritis were 83% and 93%, respectively. According to a recent study by K. Miki, a PgI/PgII ratio less than 3.0 should be considered a reliable indicator of gastric atrophy and, ultimately, of increased cancer risk; similar results were more recently outlined with regard to a Japanese population by Iijima and coworkers. In addition, according to a long-term Italian follow-up study, a PgI/PgII ratio less than 3.0 was found to be significantly correlated with both the severity and the topography of atrophy, as assessed by gastritis staging. According to that same study, the pepsinogen ratio at the patients’ enrollment significantly predicted their cancer risk, as assessed at the end of the 12-year follow-up. A meta-analysis on the sensitivity and specificity of PgI and PgII values as screening tests for advanced precancerous lesions (ie, dysplasia) were associated with a PgI/PgII ratio less than 3, with a negative predictive value (NPV) greater than 95%.
More recently, H. Tu and coworkers reported on a cohort of 2039 Chinese subjects in whom the PgI/PgII ratio was tested as a predictor of progression of gastric precancerous lesions. In that study population, the odds ratio (OR) for patients whose PgI/PgII ratio decreased 50% or more with respect to those in whom it increased 50% or more was 1.40 (confidence interval [CI] 1.08–1.81); among patients in whom both the PgII and anti– H pylori immunoglobulin G levels were increased 50% or more with respect to patients whose values decreased 50% or more, the OR was 3.18 (CI 2.05–4.93).
According to available evidence, serum pepsinogen values should never be regarded as cancer biomarkers but should be considered functional indicators of extensive mucosa atrophy and, therefore, as markers of a cancer-prone gastric microenvironment. The predictive value of pepsinogen testing is limited in patients harboring antrum-restricted atrophy, which explains those (unusual) cases in which normal PgI values are associated with overt gastric carcinoma. Moreover, as wisely observed by A. Shiotani and colleagues, the reliability of pepsinogen testing “clearly depends on the cut-off of serum pepsinogen levels as well as the definition used to identify atrophy.”
A panel of serologic tests (GastroPanel; Biohit HealthCare) including serum pepsinogens (PgI and PgII), gastrin 17 (G-17), and anti– H pylori antibodies has recently been proposed as a tool for the serologic screening (serologic biopsy) of dyspeptic patients. The rationale behind including anti-Helicobacter pylori (Hp) serology is clearly based on its contribution to the morphogenesis of the gastric atrophy. G-17 (a subfraction of total gastrin consisting of 17 amino-acids) is, instead, synthesized/secreted exclusively by gastric antral G cells; serum G-17 is expected to be significantly reduced in the event of severe antral atrophy. G-17, instead, increases significantly in hypochlorhydric patients because of severe atrophy affecting the gastric corpus mucosa. An increased serum G-17 level can, as a result, be confidently assumed to be a marker of autoimmune (corpus-restricted) atrophic gastritis. G-17 is, unfortunately, unstable in serum and requires stabilization with highly standardized procedures for sampling and processing. In populations with a low prevalence of atrophic gastritis, the NPV of the serologic panel in identifying atrophic gastritis is as high as 97% (95% CI = 95%–99%). More recently, a multicenter study testing the accuracy of the GastroPanel in assessing atrophic gastritis demonstrated an acceptable NPV (NPV = 92%; 95% CI = 86%–98%) but failed to identify 5 out of the 10 atrophic patients (sensitivity = 50%) included in the cohort of the 85 subjects studied.
The most recent (and actually not the last) step in pepsinogens’ validation as markers of atrophic gastritis was made at the Kyoto Global Consensus Conference (Kyoto, February 2014) where the experts involved unequivocally agreed on the following statement: “Serological tests (pepsinogen I and II and anti- H pylori antibody) are useful for identifying patients at increased risk for gastric cancer (Grade of Recommendation: Strong; Evidence Level: High).”
Invasive Methods
Invasive procedures for assessing GC risk are basically 2: (1) endoscopy associated to a standard biopsy protocol and (2) histology.
Endoscopy and biopsy protocols
Significant technical progress has been achieved in endoscopic approaches. Conventional endoscopy is currently considered inadequate to assess both early and advanced precancerous lesions that are assessable with high diagnostic accuracy by last-generation, image-enhanced endoscopy (chromo-endoscopy, narrow-band imaging).
Irrespective of the endoscopic instruments that are available, gastric biopsy sampling constitutes an essential step in the assessment of organic gastric diseases. The rationale behind how and where biopsy samples should be obtained is based both on normal gastric anatomy/function and the biology of gastric diseases. According to D.Y. Graham, in fact: “taking biopsies should not be an afterthought; obtaining biopsy samples is part of a logical process aimed to provide informative clinico-biologic, diagnostic, therapeutic, and prognostic information.” (Graham DY, personal communication, 2007)
The gastric mucosa includes 2 structural/functional compartments: (1) the distal mucosecreting and (2) the proximal oxyntic: this biological heterogeneity results in different patterns of gastric inflammatory diseases. As a consequence, histologic assessment of gastritis requires separate analyses of an adequate number of biopsy specimens obtained from each of the 2 mucosal compartments. At least 5 biopsies (3 from the antrum [including the incisura angularis] and 2 from the gastric body) should be available to assess both the cause and the severity of inflammatory/atrophic disease, including their risk of malignancy.
In the H pylori gastritis model, several studies support the hypothesis that atrophic/metaplastic lesions are initially located in the region of the incisura angularis. These observations support the recommendation that incisura angularis biopsy samples be obtained both at the initial assessment of precancerous lesions and while monitoring their (possible) regression after eradication; it can be assumed, in fact, that atrophic/metaplastic lesions regress following the opposite topographic sequence characterizing their development. Consistent with that view, atrophy at the incisura angularis could be considered a histologic timer of gastric disease.
Histology
Histologically confirmed extensive gastric atrophy is consistently associated with an increased risk of GC. Any strategy addressing GC secondary prevention should then specifically focus on the histologic diagnosis of early (ie, atrophy/intestinal metaplasia) and advanced (ie, IEN) precancerous lesions.
Gastric atrophy is defined as the “loss of appropriate glands.” This definition includes 2 phenotypes of atrophic transformation: (1) the shrinkage or complete disappearance of glandular units that are replaced by fibrosis of the lamina propria (ie, a reduced glandular mass with no modification of the native glandular phenotype) and/or (2) the replacement of the native glands by metaplastic ones featuring a new commitment (so-called metaplastic atrophy caused by intestinal metaplasia [IM] and/or pseudopyloric metaplasia). Metaplastic atrophy does not necessarily imply a numerical reduction in the glandular units, but the metaplastic replacement of the native glands ultimately results in a decrease in the population of glandular structures appropriate to the compartment concerned.
In 1991, an international consensus document (the Revised Sydney System) set out to standardize the histologic assessment of gastric inflammatory diseases and provided a detailed list of elementary lesions (inflammation, atrophy, intestinal metaplasia) included in the spectrum of gastric mucosa inflammatory diseases. A scoring system was also proposed for each of these lesions (graded variables).
The descriptive philosophy behind the Sydney System has recently been replaced by new approaches to gastritis histology reporting that aim to enable a clearer stratification of gastritis-associated GC risk. These new diagnostic formats suggest histologically reporting gastritis in terms of stage: by scoring atrophy/IM microscopically in both oxyntic and antral/angular biopsy samples, the staging frame (stages 0–IV) ranks gastritis according to GC risk. The staging format was unexpectedly omitted from the recent guidelines addressing the management of gastric precancerous conditions/lesions. Although those guidelines recognize the prognostic reliability of the staging approach, they base their working recommendations entirely on the topographic spread of atrophy/metaplasia, without taking into consideration the (more significant) prognostic value linked to gastritis staging. Two staging systems have been proposed for GC risk estimation: Operative Link on Gastritis Assessment (OLGA) and Operative Link on Gastric Intestinal Assessment. Both of these distinguish gastritis into 5 stages (stage 0 to stage 4), indicating a progressively increasing risk of GC.
The OLGA staging system was put forward in 2005 by an international group of pathologists and gastroenterologists. According to the OLGA proposal, the gastritis stage is obtained by combining the atrophy scores as assessed in both antral and oxyntic biopsy samples. With regard to the dyspeptic patient population, gastritis staging significantly discriminates different classes of cancer risk (low risk: stages 0, I, and II vs high risk: stages III and IV). Moreover, a significant correlation has also been demonstrated between the severity of the organic lesions (OLGA stage) and gastric mucosa functional parameters, in particular, with serum pepsinogens.
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