Beruflich Dokumente
Kultur Dokumente
Background and Study Aims: Neoplastic lesions in the diges− pearance is that of a superficial lesion. Type 0 is divided into
tive−tract mucosa are termed “superficial” when the depth of in− three categories: protruding (0 ± I), nonprotruding and nonexca−
vasion is limited to the mucosa and submucosa. The endoscopic vated (0 ± II), and excavated (0 ± III). Type 0 ± II lesions are then
appearance has a predictive value for invasion into the submuco− subdivided into slightly elevated (IIa), flat (IIb), or depressed
Corresponding Author
R. Lambert, M. D., F.R.C.P. ´ International Agency for Research on Cancer ´ 150, cours Albert Thomas ´
Lyon 69372, Cedex 08 ´ France ´ Fax: +33−4−72 73 86 50 ´ E−mail: lambert@iarc.fr
Bibliography
Endoscopy 2005; 37 (6): 570±578 Georg Thieme Verlag KG Stuttgart ´ New York ´ ISSN 0013−726X
DOI 10.1055/s−2005−861352
± The clinical relevance of the Japanese endoscopic classifica− mucosal carcinoma” (subgroups 4−3 and 4−4). Low−grade and
tion of superficial neoplasia in the digestive tract was con− high−grade dysplasia and adenoma are equivalent terms to low−
firmed in a workshop held in Paris in 2002 by a group of spe− grade and high−grade noninvasive intraepithelial neoplasia.
cialists. The conclusions were recently published, including a High−grade intraepithelial lesions have the potential to progress
descriptive atlas of endoscopic images [3]. A further meeting after a short delay into submucosal or advanced carcinoma, as
was organized in Osaka in 2003, and a simplified and updated shown in the follow−up of untreated lesions in the gastric muco−
classification is now published here. sa in Japan [6]. In summary, all high−grade neoplastic lesions (in−
vasive and noninvasive) are now included in subdivisions of the
same group 4.
Premalignant Conditions and Premalignant Lesions
Two other terms apply to the description of superficial malignant
As a rule, discrete epithelial premalignant lesions in the diges− epithelial lesions: “de novo” cancer corresponds to small (often
tive−tract mucosa are the first step in a progression to superficial less than 5 mm), flat or depressed cancerous lesions when there
malignancy and then to advanced cancer. Premalignant lesions are no adenomatous glands in the specimen, suggesting that the
Review
often develop against a background of inflammation and diffuse carcinoma has not developed from an adenomatous precursor or
alterations in the digestive−tract mucosa; these are considered to that it has rapidly lost evidence of its adenomatous origin. “Early
be risk factors for cancer and are termed “premalignant condi− cancer” is a superficial tumor with a high potential for cure. Two
tions”. Premalignant conditions in the digestive−tract mucosa in− criteria are involved: depth of invasion and lymph−node status.
clude lesions in the squamous epithelium that occur in some re− In surgical specimens, using the pTNM classification, this corre−
gions of Asia, columnar metaplasia in the esophagus, chronic sponds to an N0 intramucosal tumor in the stratified squamous
gastritis associated with Helicobacter pylori infection, chronic in− epithelium of the esophagus and to an intramucosal or submu−
Gross Morphology
Neoplastic lesions in the esophagus, stomach, and large bowel Methodology for Endoscopic Detection of Superficial 571
are called superficial when their endoscopic appearance sug− Neoplastic Lesions
gests that invasion is limited to the mucosa and submucosa. Su−
perficial, protruding lesions are also termed “polyps”; excavated Chromoendoscopy
lesions are called “ulcers”. Less conspicuous lesions (nonprotrud− The first step in the endoscopic exploration of the digestive−tract
ing and nonexcavated) are often called “flat”, but most are slight− mucosa is to identify slightly discolored areas and irregularities
ly elevated or slightly depressed. in the surface or in the microvascular network. Precise analysis
of the lesion with assessment of its boundaries and classification
Histopathology of its morphology requires chromoendoscopy, using an iodine±
Epithelial tumors developing in the digestive tract include in− potassium iodide solution (1.5 ± 2.0 %) [8] for the squamous stra−
traepithelial neoplasia (adenomas, dysplasia, premalignancy) in tified epithelium in the esophagus and an indigo carmine solu−
the mucosa and invasive lesions classified as intramucosal or tion (0.5 ± 1.0 %) [9,10] for the mucosa in the stomach and intes−
submucosal carcinomas. The progression of intraepithelial neo− tine. Other dyes include methylene blue [11 ± 13] (1 % solution),
plasia to invasive carcinoma is not invariable, and the delay can which stains intestinal metaplasia in the esophagus or stomach,
be short or long. The Vienna classification of epithelial neoplasia and acetic acid [14] (a fresh 3 % solution), which enhances the ar−
in the mucosa of the esophagus, stomach, and intestines (compa− chitecture of the columnar metaplasia in Barrett’s esophagus.
tible with the World Health Organization classification) now
provides a consensus terminology for Western and Asian specia− Magnifying Endoscopy
lists. The revised edition of the classification [2] features five dis− Recent video endoscopes with high−quality digital imaging meet
tinct groups, and neoplastic intramucosal lesions confirmed by all the requirements for the detection of superficial neoplastic le−
the pathologist are classified into groups 3 and 4, while submu− sions and for their classification into subtypes. If the endoscope
cosal carcinoma is in group 5. is equipped with an optical zoom ( 80), more or less reliable
prediction of the histological findings (optical biopsy) is possible
Group 3 includes premalignant lesions, termed “low−grade non− [15]. Magnification endoscopy with a contrast dye reveals the
invasive intraepithelial neoplasia”. Group 4 includes premalig− surface architecture of the epithelium. Magnification endoscopy
nant lesions, termed “high−grade noninvasive intraepithelial in transparency allows exploration of the microvascular network
neoplasia” (subgroups 4−1 and 4−2) and malignant lesions, [16 ± 19]. Two specific applications of magnification endoscopy
termed “invasive high−grade intraepithelial neoplasia” or “intra− are detection of intestinal metaplasia in Barrett’s esophagus
Lambert R et al. Superficial Neoplastic Lesions in the Digestive Tract ´ Endoscopy 2005; 37: 570 ± 578
[20 ± 22] and analysis of the pit pattern of the colonic epithelium
[23 ± 27]. The latter analysis method is also used for serrated ade− Table 1 The macroscopic classification of digestive−tract cancer
nomas [28, 29]. used in Japan
responding to slightly elevated, flat, and depressed lesions (Fig− lesions, with a superficial appearance at endoscopy
ure 2). Type 0 ± III is an ulcer (Figure 3). Mixed patterns with ele−
vation and depression also occur and are classified into two Protruding
Pedunculated 0 ± Ip
groups: in 0 ± IIc + 0 ± IIa lesions, most of the surface is depressed; Sessile 0 ± Is
elevation is present in a segment of the lesion at the periphery; Nonprotruding and nonexcavated
in 0 ± IIa + 0 ± IIc lesions, there is a central depression in a globally Slightly elevated 0 ± IIa
Completely flat 0 ± IIb
elevated lesion (Figure 4). The combined patterns of excavation Slightly depressed 0 ± IIc
Lambert R et al. Superficial Neoplastic Lesions in the Digestive Tract ´ Endoscopy 2005; 37: 570 ± 578
0–II c + IIa
0–I p
0–II a + II c
0–I s
Review
Type 0 ± IIc + IIa is a depressed lesion with an elevation in part of the
cut−off limit is 2.5 mm in the columnar epithelium and 1.2 mm in the
peripheral ring. Type 0 ± IIa + IIc is an elevated lesion with a central de−
stratified epithelium of the esophagus.
pression. The central depression is surrounded by an elevated ring.
When the level of the depression is higher than the mucosa adjacent
to the lesion, it is a relatively depressed lesion.
0–II a
0–II c 0–III + II c
Figure 2 Endoscopic appearance of a superficial neoplastic lesion on Figure 5 Endoscopic appearance of a superficial neoplastic lesion on
the surface of the digestive−tract mucosa: nonprotruding and nonexca− the surface of the digestive−tract mucosa; ulcer plus depression. Type
vated types, slightly elevated (0 ± IIa), completely flat (0 ± IIb), or slight− 0 ± IIc + III is a depressed lesion with a central ulcer. Type 0 ± III + IIc is an
ly depressed (0 ± IIc). The distinction between a slightly depressed le− ulcer with short depressed margins.
sion and an excavated lesion is based on the depth of the depression
from the adjacent mucosa. The cut−off limit is 1.2 mm in the columnar
epithelium and 0.5 mm in the stratified epithelium of the esophagus. 573
sed 0 ± IIc subtype is the most frequent (45 % of all lesions), and
excavated lesions (0 ± III) are uncommon (Table 3).
Pathology Control
Invasion into the submucosa occurs more frequently in protrud−
0–III ing lesions (0 ± I) or excavated lesions (0 ± III); the lowest risk is
with completely flat (0 ± IIb) lesions (Table 4). In the same Japa−
Figure 3 Endoscopic appearance of a superficial neoplastic lesion on
the surface of the digestive−tract mucosa: excavated type (0 ± III). An nese series including 1562 patients [38], the risk of metastatic
ulcer is seen. lymph nodes was assessed in relation to the depth of invasion of
lesions classified into three groups: superficial in the mucosa
(m1 or intraepithelial + m2 or microinvasive); intermediate (m3
Neoplasia in the Squamous Epithelium of the Esophagus + sm1); deep in the submucosa (sm2 + sm3). The corresponding
proportions of lymph−node metastases in the three groups were:
Endoscopic Appearance 2 %, 19 %, and 44 %. Superficial invasion (m1 + m2), which is a safe
In the squamous stratified epithelium, the elevation or depres− indication for endoscopic treatment, was found in 69 % of 0 ± IIb
sion of a superficial neoplastic lesion is estimated with a specific lesions, 39 % of 0 ± IIc lesions, 20 % of 0 ± IIa lesions, and almost
millimeter scale [3, 37], using a single jaw of a biopsy forceps (1.2 never for 0 ± I and 0 ± III lesions.
mm) as a calibrating gauge. Protruding 0 ± I lesions rise more
than 1.2 mm above the adjacent surface. Lesions less elevated In conclusion, endoscopic treatment is recommended for nonde−
than the gauge are classified as 0 ± IIa. Lesions less deep than pressed neoplastic lesions up to a diameter of 20 mm and up to
0.5 mm are classified as slightly depressed (0 ± IIc). Lesions deep− 10 mm for depressed lesions. In the histopathological assess−
er than 0.5 mm are classified as excavated (0 ± III). In the esopha− ment, a cut−off limit for the depth of invasion into the submucosa
gus, protruding lesions are not frequent and have a sessile mor− is 200 m [32].
phology (0 ± Is). Most neoplastic lesions (75 %) are nonprotrud−
ing, as shown by the analysis of 1562 surgical specimens of “su−
perficial” cancer from 143 institutions in Japan [38]: the depres−
Lambert R et al. Superficial Neoplastic Lesions in the Digestive Tract ´ Endoscopy 2005; 37: 570 ± 578
1 2 3 4 5
Table 3 Relative proportions (%) of subtypes in type 0 lesions in Ja−
epithelium pan. Series based on endoscopic analysis and a pathology
specimen
lamina propria
musc. mucosae Subtype Esophagus 1 Stomach 2 Large bowel 3
(n = 1562) (n = 2098) (n = 3644)
3, intramucosal cancer (or m3); 4, cancer with superficial invasion of ple and combined IIc types.
the submucosa (sm1); 5, cancer with deep invasion of the submucosa
(sm2 or sm3). Endoscopic mucosectomy is fully justified in situations 1
or 2. The indication is debatable in situations 3 and 4, and inappropri−
ate in situation 5, when the depth of invasion into the submucosa is
200 m.
Table 4 Relative frequency (%) of submucosal invasion in subtypes
of type 0 lesions in Japan. Series based on endoscopic
analysis and a pathology specimen
Lambert R et al. Superficial Neoplastic Lesions in the Digestive Tract ´ Endoscopy 2005; 37: 570 ± 578
Neoplasia in the Stomach (Cardia Excluded) Neoplasia in the Large Bowel
Review
[41]. Lesions combining elevation and depression are classified classified either as 0 ± IIc + IIa (depressed lesions with elevated
into two groups: depressed lesions in which most of the surface margins) or 0 ± IIa + IIc (elevated lesions with a central depres−
is depressed and there is elevation in a portion of the peripheral sion). Relatively depressed lesions are a variant of the IIa + IIc le−
ring are classified as 0 ± IIc + 0 ± IIa, while elevated lesions with a sions.
central depression encircled by the elevated ring at the periphery
are called 0 ± IIa + 0 ± II c (Figure 4). The combined patterns of ex− In the published series [3] from Niigata Hospital, protruding
cavation and depression are called 0 ± III + IIc or 0 ± IIc + III, de− polyps represented approximately 50 % of all lesions (Table 3);
Lambert R et al. Superficial Neoplastic Lesions in the Digestive Tract ´ Endoscopy 2005; 37: 570 ± 578
endoscopic technique of submucosal dissection with a needle− (0 ± IIc) lesions has an impact on the efficacy of cancer preven−
knife. The size limit for safe resection of depressed lesions is es− tion, as these lesions have a high potential for progression to in−
timated at 10 mm. At histopathological assessment, in the ab− vasive malignancy. The precursors of colorectal cancer do not
sence of adverse qualitative characteristics, a cut−off limit of consist exclusively of protruding lesions [48, 49]; a recent study
1000 m for the depth of invasion into the submucosa is a safe from Sweden suggests that more than 40 % of advanced colorec−
guideline. This requires precise identification of the position of tal cancers develop from a nonprotruding precursor [50].
the muscularis mucosae adjacent to the lesion [43]. The cut−off
value applies to sessile protruding lesions and nonprotruding le− For the endoscopist, training and experience depend on constant
sions; more flexible limits are used for polypoid precursors. interaction with the pathologist. In specimens resected at endos−
copy, the depth of invasion into the submucosa is checked and
measured with a micrometer in order to confirm the justification
Discussion for endoscopic treatment.
Quality Assurance in Diagnostic Endoscopy In the upper gastrointestinal tract, most precursors of advanced
Review
Recent video endoscope models with high resolution are suitable cancer have a nonprotruding morphology. In the absence of ad−
for early detection of the nonprotruding precursors of advanced verse qualitative criteria, the risk of lymphatic metastases is ex−
cancer. However, the proportion of false−negative procedures is tremely small when the depth of invasion into the submucosa is
far from zero. Underestimation of the role of nonprotruding le− less than 200 m in the esophagus or 500 m in the stomach.
sions as precursors of advanced colorectal cancer in Western These are the cut−off values for the safety of endoscopic muco−
populations is the result of technical differences rather than eth− sectomy.
nic ones. Nonprotruding depressed 0 ± IIc neoplastic lesions are
Lambert R et al. Superficial Neoplastic Lesions in the Digestive Tract ´ Endoscopy 2005; 37: 570 ± 578
6
Members of the Endoscopic Classification Review Group Tsukuma H, Oshima A, Narahara H et al. Natural history of early gas−
tric cancer: a non−concurrent long term follow up study. Gut 2000; 47:
618 ± 621
A. Axon, Leeds Teaching Hospitals National Health Service Trust, 7
Winawer SJ, Zauber AG, O’Brien MJ et al. The National Polyp Study: de−
Leeds, United Kingdom sign, methods, and characteristics of patients with newly diagnosed
M. D. Diebold, Centre Hospitalier Universitaire Robert DebrØ, polyps. The National Polyp Study Workgroup. Cancer 1992; 70:
Reims, France 1236 ± 1245
8
Inoue H, Rey JF, Lightdale C. Lugol chromoendoscopy for esophageal
M. Fujino, Yokohama Seamen’s Insurance Hospital, Yokohama, squamous cell cancer. Endoscopy 2001; 33: 75 ± 79
Japan 9
Kudo S, Kashida H, Tamura S et al. The problem of “flat” colonic adeno−
R. Fujita, Yokohama Seamen’s Insurance Hospital, Yokohama, ma. Gastrointest Endosc Clin N Am 1997; 7: 87 ± 98
10
Japan, Cancer Institute Hospital, Tokyo, Japan Jaramillo E, Watanabe M, Slezak P et al. Flat neoplastic lesions of the
colon and rectum detected by high resolution video−endoscopy and
R. M. Genta, Hôpitaux Universitaires de Genve, Geneva, chromoscopy. Gastrointest Endosc 1995; 42: 114 ± 122
Switzerland 11
Canto MI, Setrakian S, Willis JE et al. Methylene blue staining of dys−
J. J. Gonvers, Polyclinique MØdicale Universitaire, Lausanne, plastic and nondysplastic Barrett’s esophagus: an in vivo and ex vivo
Switzerland study. Endoscopy 2001; 33: 391 ± 400
Review
12
Kiesslich R, Hahn M, Herrmann G et al. Screening for specialized co−
M. Guelrud, Tufts±New England Medical Center, Boston, lumnar epithelium with methylene blue: chromoendoscopy in pa−
Massachusetts, USA tients with Barrett’s esophagus and a normal control group. Gastroin−
H. Inoue, Showa University Northern Yokohama Hospital, test Endosc 2001; 53: 47 ± 52
13
Yokohama City, Kanagawa, Japan Sharma P, Topalovski M, Mayo MS et al. Methylene blue chromoen−
doscopy for detection of short−segment Barrett’s esophagus. Gastroin−
M. Jung, St. Hildegardis−Krankenhaus, Mainz, Germany test Endosc 2001; 54: 289 ± 293
H. Kashida, , Showa University Northern Yokohama Hospital, 14
Lambert R, Rey JF, Sankaranarayanan R. Magnification and chromosco−
Yokohama City, Kanagawa, Japan py with the acetic acid test. Endoscopy 2003; 35: 437 ± 445
Lambert R et al. Superficial Neoplastic Lesions in the Digestive Tract ´ Endoscopy 2005; 37: 570 ± 578
31
Japanese Society for Esophageal Diseases. Guidelines for the clinical nocarcinoma of the distal stomach and esophagus. Oncology 2001;
and pathologic studies on carcinoma of the esophagus. 9th ed. Tokyo: 61: 1 ± 9
41
Kanehara, 1999 Park DI, Rhee PL, Kim JE et al. Factors suggesting malignant transfor−
32
Watanabe H, Komukai S, Ajioka Y et al. Histopathology of m3 and sm1 mation of gastric adenoma: univariate and multivariate analysis. En−
invasive squamous cell carcinoma of the esophagus, with special re− doscopy 2001; 33: 501 ± 506
42
ference to endoscopic resection [in Japanese]. Stomach Intest 1998; National Report of the Group Medical examination for digestive can−
33: 1001 ± 1009 cer in 1999 [in Japanese]. J Gastroenterol Mass Surv 2002; 40: 57 ± 76
33 43
Kobayashi M, Watanabe H, Maeo S et al. Correlation of histological Hosokawa O, Tsuda S, Kidani E et al. Diagnosis of gastric cancer up to
atypia and cancer−sprouting with vascular permeation and lymph three years after negative upper gastrointestinal endoscopy. Endosco−
nodal metastasis by our new histological classification of submucosal py 1998; 30: 669 ± 674
44
invasion by colorectal carcinomas [in Japanese]. Stomach Intest 1994; Rex DK, Cummings OW, Helper DJ et al. 5−year incidence of adenomas
29: 1151 ± 1160 after negative colonoscopy in asymptomatic average−risk persons.
34
Yokoyama J, Ajioka Y, Watanabe H et al. Lymph node metastasis and Gastroenterology 1996; 11: 1178 ± 1181
45
micrometastasis of submucosal invasive colorectal carcinoma: an in− Winawer SJ, Zauber AG, Ho MN et al. Prevention of colorectal cancer
dicator of the curative potential of endoscopic treatment. Acta Med by colonoscopic polypectomy. The National Polyp Study Workgroup.
Biol 2002; 50: 1 ± 8 N Engl J Med 1993; 329: 1977 ± 1981
35 46
Egashira Y, Yoshida T, Hirata I et al. Analysis of pathological risk factors Gorski TF, Rosen L, Riether R et al. Colorectal cancer after surveillance
Review
for lymph node metastasis of submucosal invasive colon cancer. Mod colonoscopy: false−negative examination or fast growth? Dis Colon
Pathol 2004; 17: 503 ± 511 Rectum 1999; 42: 877 ± 880
36 47
Ueno H, Mochizuki H, Hashiguchi Y et al. Risk factors for an adverse Bressler B, Paszat LF, Vinden C et al. Colonoscopic miss rates for right−
outcome in early invasive colorectal carcinoma. Gastroenterology sided colon cancer: a population−based analysis. Gastroenterology
2004; 127: 385 ± 394 2004; 127: 452 ± 456
37 48
Watanabe H, Tada T, Iwafuchi M et al. New definition and macroscopic Burgart L. Colorectal polyps and other precursor lesions: need for an
characteristics of early carcinoma of the esophagus. Stomach Intest expanded view. Gastroenterol Clin North Am 2002; 31: 959 ± 970
49
1990; 25: 1075 ± 1086 Jass JR. Histopathology of early colorectal cancer. World J Surg 2000;
38
Kodama M, Kakegawa T. Treatment of superficial cancer of the esoph− 24: 1016 ± 1021
578
Lambert R et al. Superficial Neoplastic Lesions in the Digestive Tract ´ Endoscopy 2005; 37: 570 ± 578