Nonpolypoid neoplastic lesions of the colorectal mucosa

https://doi.org/10.1016/j.gie.2008.07.052Get rights and content

Introduction

The progress in our understanding of early events in the development of colonic neoplasia is the result of 2 advances: (1) improved characterization of lesions detected at endoscopy and (2) new knowledge about the molecular biology of nonpolypoid lesions. Improved characterization of neoplastic lesions has been achieved through the addition of chromoscopy1, 2, 3, 4, 5 and high-resolution endoscopy with magnification and image processing.6, 7, 8, 9 New molecular knowledge about both sessile serrated lesions and flat adenomas has altered our understanding of the histogenesis of nonpolypoid lesions and their endoscopic management. A multidisciplinary workshop held in February 2008 in Kyoto, Japan, explored new aspects of our knowledge. This text summarizes the debate and ultimately the consensus among experts in endoscopy, pathology, and molecular biology of the colon.

In 1975, Muto et al10 described the histologic transition from a precursor adenomatous polyp to a confirmed colorectal cancer. Previous opinion, that colorectal cancer develops through a single pathway, has now been challenged, and it is clear that colorectal cancer can develop through multiple pathways, as reviewed by Jass11 and Jass et al.12 The morphology of premalignant colonic lesions depends on the direction of proliferating cell growth. Essentially, 3 types of lesions are now recognized: polypoid, nonpolypoid, and depressed. Polypoid lesions grow above the surface of the mucosa, rather than below, and the volume of the polypoid component appears to correlate with the histologic stage, as shown in the large series issued from endoscopy and pathology units in Japan and listed in the Paris classification.13, 14 Nonpolypoid lesions may grow flat or slightly elevated and, eventually, may grow and progress to polypoid lesions or to laterally spreading tumors. Depressed lesions deserve special attention because of the difficulty in their detection, the need for special techniques (mucosectomy) to remove them by endoscopy, and a recognized increased risk of rapid progression to cancer, independent of size, as shown in endoscopy and pathology units in Japan.13, 14 Nonpolypoid, depressed lesions progress in depth rather than above the surface of the mucosa, and submucosal invasion is frequent, even for small lesions (Figs. 1 and 2).

Sporadic colorectal neoplasia results from the disruption of normal cellular growth and senescence at a molecular level. In 1990, Fearon and Vogelstein15 demonstrated that a mutation within the adenomatous polyposis coli (APC) tumor-suppressor gene initiated one of the major neoplasia pathways. This mutation was linked to chromosomal instability (CIN) and loss of heterozygosity (LOH). Subtle molecular differences cause alternative growth patterns, such as polypoid or nonpolypoid (including the flat adenoma and flat cancer), and they, subsequently, will be discussed.

In the last decade, the serrated pathway has been described as an alternative pathway to colorectal cancer. Serrated lesions refer both to hyperplastic (HP) (nonneoplastic) lesions, often called HP polyps, and sessile serrated lesions, often called sessile serrated adenomas (SSAs); the latter are considered the precursor for microsatellite instable (MIS) cancers. An early event in the growth of sessile-serrated lesions is an inactivating mutation within the BRAF gene encoding the B-RAF protein kinase. Progression from nondysplastic sessile-serrated lesions to neoplasia requires epigenetic silencing of hMLH1, one of the mismatch repair (MMR) genes. Inactivating methylation of hMLH1 disrupts the MMR cascade, which results in the accumulation of mutations in a variety of genes, some of which lead to neoplasia and MIS cancers.

Section snippets

Endoscopic classification of polypoid and nonpolypoid superficial lesions

The morphology of superficial neoplastic or nonneoplastic lesions in the colorectal mucosa is protruding (polypoid) or flat (nonpolypoid). Premalignant and malignant neoplastic lesions of the digestive mucosa are called superficial when their appearance at endoscopy suggests that their depth is limited to the mucosa (m) or submucosa (sm). Nonpolypoid (flat) small neoplastic lesions are frequent in human beings, and some of them show a fast progression to cancer, in spite of maintaining a small

Adenoma

An adenoma is a premalignant lesion that shows intraepithelial neoplasia without invasion of the mucosal stroma and is always associated with cytologic neoplasia. The identification of an adenoma is based on 2 types of alterations: structural and cytologic. The structural or architectural features include simple-to-complex crowding of glands, lateral expansion, and irregularity. According to their architecture, adenomas are classified as tubular, tubulovillous, or villous types: at least 20% of

Histologic classification of serrated lesions

The term “serrated” refers to the histologic appearance of a variety of polyps, the edge of which has a wavy or serrated contour. The specific architectural feature deserving the term “serrated” is the irregular and enlarged upper part of the crypts, which are notched like a saw with teeth pointing toward the center of the lumen; the serration index describes the severity of the architectural defect. There is some confusion in the classification of serrated lesions as neoplastic or

Classification of the surface pattern of nonpolypoid lesions on magnifying endoscopy

Magnification of the endoscopic image at a power ×80 or more combines optical and electronic technologies and displays the microarchitecture (pits and crests) of the mucosa, which allows classification with clinical relevance for the “pit pattern.” Magnification can be coupled with image processing. In the narrow-band imaging (NBI) technique (Olympus Medical Systems Corp, Tokyo, Japan), a special set of filters is interposed on the optical path, and the incident photons are emitted in 2 narrow

Genetic factors that control the growth of tumors in the colorectal mucosa

Considerable progress78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96 has occurred during the most recent years in the description of genetic events for the adenoma-carcinoma sequence, the HP serrated carcinoma sequence, hereditary cancer,97, 98, 99 and cancer in inflammatory bowel disease.100, 101, 102, 103, 104 A link has been established between the genetic events that control the development of the neoplastic lesions and their morphology (Tables 10 and 11).

Role of aberrant crypt foci on the origin of colorectal carcinoma

Aberrant crypt foci (ACF) are defined as small clusters (2 or more) of enlarged crypts with dilated openings, which rise above the adjacent mucosa.105, 106, 107, 108, 109, 110, 111, 112, 113, 114 ACF can be identified and numbered at the surface of the mucosa with magnification chromoendoscopy, by using indigo carmine solution at 0.2%, or methylene blue solution at 0.01%. The numeration is usually performed with a high-power field, which may vary according to the material used and the

Endoscopic prevalence of superficial neoplastic lesions

The prevalence of superficial lesions detected during complete colonoscopy in the colorectal mucosa of asymptomatic patients is high in Japan.115, 116 In a study conducted at the National Cancer Center in Tokyo in 2004 by the Research Cancer Center for Prevention and Screening,116 the prevalence of neoplastic lesions was 60% in 2968 patients. In Western countries, the figures depend on the recourse to high-resolution endoscopy and image processing during colonoscopy. In the United States,

Cancer in polypoid and nonpolypoid lesions

The proportion of cancer with invasion of submucosa was analyzed in relation to morphology in endoscopic series from Japan. At the Akita and Yokohama Northern Hospitals (Table 13), the proportion of cancers with invasion of the submucosa was very high in depressed nonpolypoid lesions: 35.9% (210 of 585 lesions). In the series of the Hiroshima University Hospital (Table 14), the figure was also very high for the same category of lesions: 27% (77 of 285 lesions). In contrast, in both series, the

Evaluation of submucosal invasion from the superficial pit pattern

The pit pattern of the colonic mucosa can be assessed by using magnifying endoscopy in conjunction with chromoscopy or NBI. The studies conducted by various endoscopy groups in Japan, with histologic controls, confirmed that some categories of the pit pattern are predictive of cancer extension into the submucosa. In 7740 neoplastic colorectal lesions analyzed at the Northern Yokohama Hospital (Table 19), submucosal cancer was confirmed by histology in 33.7% of lesions that showed a category V

Protection afforded by colonoscopy against colorectal cancer

The role of colonoscopy in the prevention of colorectal cancer depends on its double function: first, in the diagnosis of cancer at an early curable stage and for the diagnosis of the precursors of cancer—this occurs in opportunistic screening of asymptomatic patients and in organized screening after a positive fecal occult blood test; second, as a therapeutic procedure that allows the endoscopic resection of precursors of cancer and of superficial cancers without massive invasion of the

Strategy of endoscopic diagnosis

Superficial neoplastic lesions of the colorectal mucosa were first described by using rigid rectosigmoidoscopes, then with fiber-colonoscopes. Since then, there has been a considerable technical evolution, and the most recent electronic video colonoscopes offer high resolution, magnification, and image processing, including the NBI technique. Because of this, the proportion of patients with abnormal findings at colonoscopy is higher than in previous reports; yet seeing more does not mean more

Acknowledgment

The initiative to conduct the workshop was stimulated by the discussions about the program developed by the European Commission for the Development of Quality Assurance for Colorectal Cancer Screening.

First page preview

First page preview
Click to open first page preview
View PDF

References (154)

  • H. Goto et al.

    Proportion of de novo cancers among colorectal cancers in Japan

    Gastroenterology

    (2006)
  • T. Matsumoto et al.

    Serrated adenoma of the colorectum: colonoscopic and histologic features

    Gastrointest Endosc

    (1999)
  • S. Oka et al.

    Clinicopathologic and endoscopic features of colorectal serrated adenoma: differences between polypoid and superficial types

    Gastrointest Endosc

    (2004)
  • R. Beach et al.

    BRAF mutations in aberrant crypt foci and hyperplastic polyposis

    Am J Pathol

    (2005)
  • K.J. Spring et al.

    High prevalence of sessile serrated adenomas with BRAF mutations: a prospective study of patients undergoing colonoscopy

    Gastroenterology

    (2006)
  • M. Hermsen et al.

    Colorectal adenoma to carcinoma progression follows multiple pathways of chromosomal instability

    Gastroenterology

    (2002)
  • T. Morita et al.

    Molecular analysis of diminutive, flat, depressed colorectal lesions: are they precursors of polypoid adenoma or early stage carcinoma?

    Gastrointest Endosc

    (2002)
  • T. Takahashi et al.

    Flat-type colorectal advanced adenomas (laterally spreading tumors) have different genetic and epigenetic alterations from protruded-type advanced adenomas

    Mod Pathol

    (2007)
  • S. Hiraoka et al.

    Laterally spreading type of colorectal adenoma exhibits a unique methylation phenotype and K-ras mutations

    Gastroenterology

    (2006)
  • J.D. Mueller et al.

    Loss of heterozygosity and microsatellite instability in de novo versus ex-adenoma carcinomas of the colorectum

    Am J Pathol

    (1998)
  • S.R. Brown et al.

    Chromoscopy versus conventional endoscopy for the detection of polyps in the colon and rectum

    Cochrane Database Syst Rev

    (2007 Oct 17)
  • D.P. Hurlstone et al.

    Detecting diminutive colorectal lesions at colonoscopy: a randomised controlled trial of pan-colonic versus targeted chromoscopy

    Gut

    (2004)
  • M.G. Lapalus et al.

    Does chromoendoscopy with structure enhancement improve the colonoscopic adenoma detection rate?

    Endoscopy

    (2006)
  • R. Kiesslich et al.

    Chromoendoscopy with indigocarmine improves the detection of adenomatous and nonadenomatous lesions in the colon

    Endoscopy

    (2001)
  • H.M. Chiu et al.

    A prospective comparative study of narrow-band imaging, chromoendoscopy, and conventional colonoscopy in the diagnosis of colorectal neoplasia

    Gut

    (2007)
  • M.Y. Su et al.

    Comparative study of conventional colonoscopy, chromoendoscopy, and narrow-band imaging systems in differential diagnosis of neoplastic and nonneoplastic colonic polyps

    Am J Gastroenterol

    (2006)
  • J.J. Tischendorf et al.

    Value of magnifying chromoendoscopy and narrow band imaging (NBI) in classifying colorectal polyps: a prospective controlled study

    Endoscopy

    (2007)
  • T. Muto et al.

    The evolution of cancer of the colon and rectum

    Cancer

    (1975)
  • J.R. Jass

    Colorectal cancer: a multipathway disease

    Crit Rev Oncog

    (2006)

  • The Paris endoscopic classification of superficial neoplastic lesions: esophagus, stomach, and colon (November 30 to December 1, 2002)

    Gastrointest Endosc

    (2003)
  • Endoscopic Classification Review Group

    Update on the Paris classification of superficial neoplastic lesions in the digestive tract

    Endoscopy

    (2005)
  • C.A. Rubio et al.

    Adenocarcinoma of the cecum with Crohn's-like features in baboons

    Anticancer Res

    (1998)
  • C.A. Rubio et al.

    Difference in histology and size in colonic tumors of rats receiving two different carcinogens

    J Environ Pathol Toxicol Oncol

    (1994)
  • J. Shetye et al.

    The chronological appearance of flat colonic neoplasias in rats

    In Vivo

    (2004)
  • S. Kudo et al.

    Depressed type of colorectal cancer

    Endoscopy

    (1995)
  • S. Kudo et al.

    Treatment of colorectal sm carcinoma

    Stomach Intestine

    (1984)
  • S. Kudo

    Endoscopic mucosal resection of flat and depressed types of early colorectal cancer

    Endoscopy

    (1993)
  • S. Kudo

    Early colorectal cancer

    (1996)
  • S. Kudo et al.

    Superficial depressed type (IIc) of colorectal carcinoma

    Gastroenterol Endosc

    (1986)
  • R.J. Schlemper et al.

    The Vienna classification of gastrointestinal epithelial neoplasia

    Gut

    (2000)
  • M.F. Dixon

    Gastrointestinal epithelial neoplasia: Vienna revisited

    Gut

    (2002)
  • R. Kikuchi et al.

    Management of early invasive colorectal cancer. Risk of recurrence and clinical guidelines

    Dis Colon Rectum

    (1995)
  • T. Muto et al.

    Small “flat adenoma” of the large bowel with special reference to its clinicopathologic features

    Dis Colon Rectum

    (1985)
  • T. Yao et al.

    Depressed adenoma of the colorectum: analysis of proliferative activity using immunohistochemical staining for proliferating cell nuclear antigen (PCNA)

    Pathol Int

    (1994)
  • Y. Ajioka et al.

    Early colorectal cancer with special reference to the superficial nonpolypoid type from a histopathologic point of view

    World J Surg

    (2000)
  • T. Ogawa et al.

    Genetic instability on chromosome 17 in the epithelium of non-polypoid colorectal carcinomas compared to polypoid lesions

    Cancer Sci

    (2006)
  • S. Oshiba et al.

    Minute gastric cancer

    Tohoku J Exp Med

    (1976)
  • T. Shimoda et al.

    Early colorectal carcinoma with special reference to its development de novo

    Cancer

    (1989)
  • L. Bedenne et al.

    Adenoma—carcinoma sequence or “de novo” carcinogenesis? A study of adenomatous remnants in a population-based series of large bowel cancers

    Cancer

    (1992)
  • C.D. Chen et al.

    A case-cohort study for the disease natural history of adenoma-carcinoma and de novo carcinoma and surveillance of colon and rectum after polypectomy: implication for efficacy of colonoscopy

    Br J Cancer

    (2003)

    • Cited by (450)

    • Endoscopic features with associated histological and molecular alterations in serrated polyps with dysplasia: Retrospective analysis of a tertiary case series

      2024, Digestive and Liver Disease

    • Low delayed bleeding and high complete closure rate of mucosal defects with the novel through-the-scope dual-action tissue clip after endoscopic resection of large nonpedunculated colorectal lesions (with video)

      2024, Gastrointestinal Endoscopy

    • Endoscopic Diagnosis of Superficial Gastrointestinal Cancer

      2024, Gastrointestinal Endoscopy Clinics of North America

    • The Surface Morphology of Large Nonpedunculated Colonic Polyps Predicts Synchronous Large Lesions

      2023, Clinical Gastroenterology and Hepatology

    • Safety and feasibility of same-day discharge after endoscopic submucosal dissection: a Western multicenter prospective cohort study

      2023, Gastrointestinal Endoscopy

    • Curative Effect Analysis of Endoscopic Submucosal Dissection in Giant Laterally Spreading Rectal Tumors

      2024, Journal of Clinical Gastroenterology
    View all citing articles on Scopus

    Current affiliations: Hiroaki Fujii, MD, Department of Pathology (II), Juntendo University School of Medicine, Tokyo, Japan. Takahiro Fujii, MD, TF Clinic, Ginza, Tokyo, Japan. Hiroshi Kashida, MD, Shin ei Kudo, MD, Digestive Disease Center, Northern Yokohama Hospital, Showa University, Yokohama, Japan. Takahisa Matsuda, MD, Division of Endoscopy, Tadakazu Shimoda, MD, Clinical Laboratory Division, National Cancer Centre Hospital, Tokyo, Japan. Masaki Mori, MD, PhD, FACS, Department of Surgery, Medical Institute of Bioregulation, Kyushu University Hospital, Beppu, Japan. Hiroshi Saito, MD, Cancer Screening, Technology Division, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo, Japan. Shinji Tanaka, MD, Department of Endoscopy, Hiroshima University Hospital, Hiroshima, Japan. Hidenobu Watanabe, MD, Division of Molecular and Diagnostic Pathology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan. Joseph J. Sung, MD, Institute of Digestive Diseases, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong. John I. Allen, MD, Medical Director, Minnesota Gastroenterology, University of Minnesota School of Medicine, Minneapolis, Minnesota, USA. Andrew D. Feld, MD, Clinical Associate Professor of Medicine, Central Division of Gastroenterology, Group Health Cooperative, University of Washington, Seattle, Washington, USA. John M. Inadomi, MD, Director, GI Health Outcomes Research Program, University of California, San Francisco, Division of Gastroenterology, San Francisco General Hospital, San Francisco, California, USA. Michael J. O'Brien, MD, Department of Pathology, Boston University Medical Center, Boston, Massachusetts, USA. David A. Lieberman, MD, Division of Gastroenterology, Portland VA Hospital, Portland, Oregon, USA. David F. Ransohoff, MD, Bioinformatics, Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA. Roy M. Soetikno, MD, Gastroenterology Section, Veterans Affairs, Palo Alto Health Care System, Palo Alto, California, USA. George Triadafilopoulos, MD, DSc, Clinical Professor of Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California, USA. Ann Zauber, PhD, Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. Claudio Rolim Teixeira, MD, Medical Director, Endoscopy Unit of Rio Grande do Sul, Foundation of Gastroenterology, Porto Alegre, Rio Grande do Sul, Brazil. René Lambert, MD, FRCP, Group of Screening, International Agency for Research on Cancer, Lyon, France. Jean François Rey, MD, Department of Hepatology and Gastroenterology, Institut Arnault Tzanck, Saint Laurent du Var, France. Edgar Jaramillo, MD, Department of Gastroenterology and Hepatology, Karolinska Universitetssjukhus, Stockholm, Sweden. Carlos A. Rubio, MD, PhD, Gastrointestinal and Liver Pathology, Research Laboratory, Department of Pathology, Karolinska Institute and University Hospital, Stockholm, Sweden. Andre Van Gossum, MD, Department of Gastroenterology, Clinic of Intestinal Diseases and Nutritional Support, Hopital Erasme, Brussels, Belgium. Michael Jung, MD, St Hildegardis Krankenhaus, Klinik für Innere Medizin und Gastroenterologie, Johannes-Gutenberg-Universitat, Mainz, Germany. Michael Vieth, MD, Institute of Pathology, Klinikum Bayreuth, Bayreuth, Germany. Jeremy R. Jass, MD, Professor of Gastrointestinal Pathology, Department of Cellular Pathology, St Mark's Hospital, Imperial College London, Harrow, England. Paul D. Hurlstone, MD, FRCP, Consultant Endoscopist, Reader in Gastroenterology, Royal Hallamshire Hospital, Sheffield, England

    View full text
    Copyright © 2008 American Society for Gastrointestinal Endoscopy. Published by Mosby, Inc. All rights reserved.