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Precancerous lesions in the stomach: From biology to clinical patient management

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Abstract

Gastric cancer is the final step in a multi-stage cascade triggered by long-standing inflammatory conditions (particularly Helicobacter pylori infection) resulting in atrophic gastritis and intestinal metaplasia: these lesions represent the cancerization field in which (intestinal-type) gastric cancer develops. Intraepithelial neoplasia is consistently recognized as the phenotypic bridge between atrophic/metaplastic lesions and invasive cancer. This paper addresses the epidemiology, pathology, molecular profiling, and clinical management of advanced precancerous gastric lesions.

Introduction

Over the last 25 years, a growing body of evidence has shown that epithelial malignancies are the final step along a complex biological path involving a progressive (multi-factorial) accumulation of genotypic and phenotypic changes, and sporadic gastric cancer is by no means an exception [1], ∗[2].

Less than 10% of gastric cancers (GC) are hereditary. The genetic factors involved in familial malignancies remain largely unknown, although specific, well-characterized mutations have been thoroughly described in a subset of patients.

By far the majority of GCs are sporadic, most of them triggered by long-standing inflammatory conditions (due primarily to infectious, but also to chemical agents or autoimmune diseases) resulting in a mainly-unknown interplay of molecular and phenotypic derangements. Such a natural history, as at first described by Pelayo Correa, is currently known as Correa's multi-stage cascade of gastric oncogenesis. According to Correa, long-standing mucosa inflammation may result into gastric atrophy/intestinalization, which may further progress into advanced precancerous lesions (APLs; currently distinguished into low-grade [LG-IEN] and high-grade intraepithelial neoplasia [HG-IEN]); these spectrum of intraepithelial neoplastic changes may eventually develop into invasive cancer [3]. APLs are conventionally identified as phenotypic alterations bridging the (phenotypic/genotypic) gap between regenerative/metaplastic changes and invasive cancer (Fig. 1) [1], ∗[2]. In the Western literature, these phenotypic lesions were originally labelled as ‘epithelial dysplasia’. For the time being, detecting and ablating gastric APLs represent the most reliable strategy for the secondary cancer prevention.

This paper addresses the basic information (i.e.: epidemiology, pathology, molecular profiling) on the natural history of gastric precancerous lesions, also providing the biological rationale for their follow-up and treatment.

Section snippets

Precancerous conditions & precancerous lesions in the gastric mucosa

As in other areas of the gastrointestinal tract, so too within the gastric mucosa, a basic distinction is drawn between precancerous conditions and precancerous lesions. According to Basil Morson, a precancerous condition, ‘…is best regarded as a clinical state associated with a significantly increased risk of cancer, whereas a precancerous lesion is a histological abnormality in which cancer is more likely to occur … In many clinical conditions with an increased risk of cancer, there is also

Gastric atrophy (& atrophic gastritis)

The two ‘major’ compartments of the gastric mucosa feature different populations of native glands (mucosecreting in the antrum, oxyntic in the corpus). Gastric atrophy is defined as the ‘loss of appropriate glands’ [13]. This definition basically includes two phenotypes of gastric mucosa atrophy: (i) shrinkage or complete disappearance of glandular units, replaced by fibrotic expansion of the lamina propria (i.e. a reduced glandular mass, with no modification of the native cell phenotype); or

Gastric dysplasia: original definition and basic morphology

Gastric adenocarcinoma may coexist with cyto-architectural changes in the adjacent glands, showing a degree of (de-)differentiation somewhere between that of the native mucosa and that of the cancer. The Western literature defined such phenotypic changes as epithelial dysplasia ∗[4], [23], [24], [25], [26], [27], [28], [29], [30], [31], while Japanese authors speak of borderline lesions, atypical epithelium, or Group 3 lesions [32], [33], [34]. The topographical contiguity and morphological

Molecular pathology of gastric intraepithelial neoplasia

Molecular typing of gastric IEN has reinforced the conviction that these lesions belong to the same biological spectrum as their invasive counterpart. The most widely accepted theory is that non-invasive neoplastic cells derived from previously-intestinalized (metaplastic) epithelia. These cancer-oriented cells have recently revealed a stem cell nature. In fact, an experimental model of chronic Helicobacter pylori-related gastritis demonstrated that bone-marrow-derived cells may home onto the

Precancerous lesions: treatment and (possible) reversion

The clinical management of precancerous gastric lesions is controversial. The related ‘operative inconsistency’ results mainly from the unreliable quantification of the cancer risk associated with the precancerous condition, and from the difficulty of assessing the clinical benefit achievable with surveillance strategies.

A nationwide Dutch study on patients with precancerous gastric lesions showed that endoscopic/histological re-assessments were performed in 26%, 28%, 38% and 61% of patients

Screening and surveillance of precancerous gastric lesions

In clinical practice, surveillance strategies for precancerous gastric lesions are currently inconsistent, and are often disregarded ∗[58], [59]. The declining incidence of precancerous gastric lesions (particularly in the industrialized word), variables relating to the health care systems in different countries, inconsistencies in cost–benefit assessments, the identification of different target patient populations, different methods being used to implement screening/surveillance strategies,

Gastric precancerous lesions in clinical practice

No evidence-based guidelines are available as yet to support a particular clinical strategy in response to a histological diagnosis of gastric IEN. Given the differences in the diagnostic criteria, the Japanese experience cannot be wholly exported to the Western world ∗[38], [109], [110].

Based on current knowledge, the following strategies can be considered for the clinical management of atrophic gastritis and intestinal metaplasia:

  • 1.

    H. pylori eradication is indicated in patients with atrophic

Conflict of interest

The authors have no conflict of interest to declare.

References (115)

  • S.A. McDonald et al.

    Mechanisms of field cancerization in the human stomach: the expansion and spread of mutated gastric stem cells

    Gastroenterology

    (2008)
  • Y.Q. Bai et al.

    Ectopic expression of homeodomain protein CDX2 in intestinal metaplasia and carcinomas of the stomach

    Cancer Lett

    (2002)
  • F. Tava et al.

    Type or extension of intestinal metaplasia and immature/atypical “indefinite-for-dysplasia” lesions as predictors of gastric neoplasia

    Hum Pathol

    (2006)
  • A.C. de Vries et al.

    The use of clinical, histologic, and serologic parameters to predict the intragastric extent of intestinal metaplasia: a recommendation for routine practice

    Gastrointest Endosc

    (2009)
  • M. Rugge et al.

    Staging gastritis: an international proposal

    Gastroenterology

    (2005)
  • P. Correa

    A human model of gastric carcinogenesis

    Cancer Res

    (1988)
  • P. Correa

    The biological model of gastric carcinogenesis

    IARC Sci Publ

    (2004)
  • P. Correa

    Human gastric carcinogenesis: a multistep and multifactorial process – First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention

    Cancer Res

    (1992)
  • B.C. Morson et al.

    Precancerous conditions and epithelial dysplasia in the stomach

    J Clin Pathol

    (1980)
  • B. Humar et al.

    E-cadherin deficiency initiates gastric signet-ring cell carcinoma in mice and man

    Cancer Res

    (2009)
  • M. Barber et al.

    Mechanisms and sequelae of E-cadherin silencing in hereditary diffuse gastric cancer

    J Pathol

    (2008)
  • D.G. Huntsman et al.

    Early gastric cancer in young, asymptomatic carriers of germ-line E-cadherin mutations

    N Engl J Med

    (2001)
  • G. Oberhuber et al.

    Gastric polyps: an update of their pathology and biological significance

    Virchows Arch

    (2000)
  • K. Dirschmid et al.

    Why is the hyperplastic polyp a marker for the precancerous condition of the gastric mucosa?

    Virchows Arch

    (2006)
  • D.Y. Graham et al.

    Long-term proton pump inhibitor use and gastrointestinal cancer

    Curr Gastroenterol Rep

    (2008)
  • K. Borch et al.

    Benign gastric polyps: morphological and functional origin

    Dig Dis Sci

    (2003)
  • M.F. Dixon et al.

    Classification and grading of gastritis. The updated Sydney System. International Workshop on the Histopathology of Gastritis, Houston 1994

    Am J Surg Pathol

    (1996)
  • B. Ruiz et al.

    Morphometric assessment of gastric antral atrophy: comparison with visual evaluation

    Histopathology

    (2001)
  • M. Rugge et al.

    Gastric mucosal atrophy: interobserver consistency using new criteria for classification and grading

    Aliment Pharmacol Ther

    (2002)
  • A.B. Price

    The Sydney System: histological division

    J Gastroenterol Hepatol

    (1991)
  • H.M. El-Zimaity et al.

    Gastric intestinal metaplasia: subtypes and natural history

    J Clin Pathol

    (2001)
  • G.J. Offerhaus et al.

    Observer agreement on the grading of gastric atrophy

    Histopathology

    (1999)
  • J.R. Jass et al.

    The mucin profiles of normal gastric mucosa, intestinal metaplasia and its variants and gastric carcinoma

    Histochem J

    (1981)
  • W.K. Leung et al.

    Factors predicting progression of gastric intestinal metaplasia: results of a randomised trial on Helicobacter pylori eradication

    Gut

    (2004)
  • M. Rugge et al.

    Autoimmune gastritis: histology phenotype and OLGA staging

    Aliment Pharmacol Ther

    (2012)
  • W. Oehlert et al.

    Gastric mucosal dysplasias: what is their clinical significance?

    Dtsch Med Wochenschr

    (1975)
  • J.R. Jass

    A classification of gastric dysplasia

    Histopathology

    (1983)
  • S.C. Ming et al.

    Gastric dysplasia. Significance and pathologic criteria

    Cancer

    (1984)
  • R.H. Riddell

    Premalignant and early malignant lesions in the gastrointestinal tract: definitions, terminology, and problems

    Am J Gastroenterol

    (1996)
  • K.J. Lewin

    Nomenclature problems of gastrointestinal epithelial neoplasia

    Am J Surg Pathol

    (1998)
  • R.H. Riddell et al.

    Problems arising from Eastern and Western classification systems for gastrointestinal dysplasia and carcinoma: are they resolvable?

    Histopathology

    (1998)
  • G.Y. Lauwers et al.

    Gastric epithelial dysplasia

    Gut

    (1999)
  • K. Takagi et al.

    Polypoid lesions of the stomach – with special reference to atypical epithelial lesions

    Gan No Rinsho

    (1967)
  • T. Nagayo

    Histological diagnosis of biopsied gastric mucosae with special reference to that of borderline lesions

    Gann Monogr

    (1971)
  • Japanese classification of gastric carcinoma

    (1995)
  • C.M. Fenoglio-Preiser et al.

    Gastric carcinoma

  • M. Rugge et al.

    Gastric dysplasia: the Padova international classification

    Am J Surg Pathol

    (2000)
  • M. Fassan et al.

    Lesions indefinite for intraepithelial neoplasia and OLGA staging for gastric atrophy

    Am J Clin Pathol

    (2012)
  • R.J. Schlemper et al.

    The Vienna classification of gastrointestinal epithelial neoplasia

    Gut

    (2000)
  • F.T. Bosman et al.

    World Health Organization classification of tumours of the digestive system

    (2010)
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