Early Neoplasias of the Gastrointestinal Tract Endoscopic Diagnosis and Therapeutic Decisions Springer US (2014)

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Endoscopic Diagnosis and 
Therapeutic Decisions
Early Neoplasias 
of the 
Gastrointestinal Tract
Frieder Berr 
Tsuneo Oyama 
Thierry Ponchon 
Naohisa Yahagi 
Editors
 Early Neoplasias of the Gastrointestinal Tract 
 
 Frieder Berr  Tsuneo Oyama 
 Thierry Ponchon  Naohisa Yahagi 
 Editors 
 Early Neoplasias of the 
Gastrointestinal Tract 
 Endoscopic Diagnosis and 
Therapeutic Decisions 
 ISBN 978-1-4614-8291-8 ISBN 978-1-4614-8292-5 (eBook) 
 DOI 10.1007/978-1-4614-8292-5 
 Springer New York Heidelberg Dordrecht London 
 Library of Congress Control Number: 2014945354 
 © Springer Science+Business Media New York 2014 
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 Printed on acid-free paper 
 Springer is part of Springer Science+Business Media (www.springer.com) 
 Editors 
 Frieder Berr 
 Department of Internal Medicine I 
 Paracelsus Medical University/Salzburger 
Landeskliniken 
 Salzburg 
 Austria 
 Tsuneo Oyama 
 Department of Endoscopy 
 Saku Central Hospital 
Advanced Care Center 
 Saku 
 Nagano 
 Japan 
 Thierry Ponchon 
 Department of Digestive Diseases 
 Hôpital Eduard Herriot 
 Lyon 
 France 
 Naohisa Yahagi 
 Division of R&D for Minor Invasive 
Treatment 
 Keio University School of Medicine 
 Shinjuku-ku 
 Tokyo 
 Japan 
 This book is dedicated to Dr. Shin-ei Kudo, 
Haruhiro Inoue, Yasushi Sano and Shinji 
Tanaka as exponents of the generation of 
originary researchers in Japan that has 
developed image-enhanced endoscopic 
analysis of early gastrointestinal cancers. 
 
 
vii
 Pref ace 
 We only fi nd what we’re prepared to look for 
 Cancer has traditionally been defi ned by proof of invasively growing dysplastic 
epithelia in the Western world, and gastrointestinal oncology has attempted to beat 
cancer at the invasive stage. Any mucosa-invasive lesion (pM2/3) must yet have a 
non-invasive precursor lesion. In Japan, therefore, cancer has been defi ned by cyto-
logic criteria – severely dysplastic epithelial cells – allowing earlier diagnosis in 
even the pre-invasive stage. Gastrointestinal oncology has emphasized in Japan the 
concept of early cancer certainly curable by resection, and endoscopic diagnostics 
have been pushed to detect the earliest, barely visible intraepithelial neoplasias. 
Hence, in many centers in Japan, more than 70 % of GI cancers are now diagnosed 
as early cancers, whereas much less (<40 %) in Western countries. 
 For more than a generation, early diagnosis of cancer has been core research 
promoted by National Societies for Gastric, Esophageal, and Colorectal Cancer in 
Japan. Enormous data has accumulated on early cancers resected for cure with 
extended lymphadenectomy and specimens precisely measured for mucosal or sub-
mucosal invasion. Surface microscopic measurements systematically characterized 
surface structure of early cancer and adjacent mucosa. At the same time, Japan 
became leading in image-enhanced as well as magnifi cation endoscopy on a supe-
rior technical level. Successful research followed on how to accurately predict the 
histologic type of neoplasias from the endoscopic aspect of mucosal surface and 
microvascular architecture. Research defi ned organ-specifi c criteria for curative 
snare-resection of small early mucosal cancers, and developed endoscopic electro-
surgery – endoscopic submucosal dissection, ESD – in order to resect wider spread-
ing mucosal cancer. Now, Japan’s experts mastermind enhanced endoscopic 
diagnostics and electrosurgery for early cancers. 
 This is the start of a new era in gastrointestinal oncology and the time to have it 
transferred from East Asia to the Western world. Western endoscopists are all fasci-
nated by the ease and skill how to resect mucosal cancers with ESD and wish to 
perform ESD as well. Frankly, diagnosis must always precede treatment – an old 
viii
clinical rule – and half of the success of any operator is credited to his competence 
in diagnosis and decision making before operation. Nevertheless, it takes a sus-
tained training effort to achieve competence and skills to analyze stage and lateral 
spread of early neoplasias almost as accurately as leading experts from Japan. This 
book attempts now to convey this endoscopic knowledge and skills also to Western 
endoscopists, in order to enhance detection and diagnostic accuracy for early gas-
trointestinal neoplasias. 
 Based on cooperation with the inventors of hook and dual knife, Drs. Oyama and 
Yahagi, the co-editors had for the past 5 years the privilege to organize annual train-
ing in ESD techniques, and courses in advanced endoscopic detection and decision- 
making for resection of early GI cancers. Their guidance inspired us to compile the 
most common endoscopic classifi cations and diagnostic approaches to early 
neoplasias. 
 The aim of this book is to raise the detection rate of minute cancers, size less than 
5 mm, and the diagnostic competence for decision making on the resection strate-
gies. Nevertheless, the text is basic and useful for both, to update interventional 
endoscopists as well as to educate novices striving for endoscopic skills. Those 
involved in training for clinical ESD should thoroughly sharpen their diagnostic 
repertoire and proceed to the atlas Endoscopic Diagnosis of Gastric Adenocarcinoma 
for ESD by Tsuneo Oyama. Within the past year, high-end magnifying and image- 
enhancing endoscopes as good as in Japan have become available all over the 
Western world. We hope this book comes in time to spur sustainable enthusiasm for 
accurate image-enhanced magnifying endoscopy of early gastrointestinal cancers. 
May the effort serve the needs of the patients, and lead the art and science of endos-
copy ahead to battle cancer. 
 Salzburg, Austria Frieder Berr, on behalf of the editors
January 26, 2014 
 
Preface
ix
 Acknowledgements 
 The special thanks of the editors and authors go to the Leonie-Wild Foundation, 
Heidelberg, for support andto all who have relentlessly contributed to text and fi g-
ures of the book, in particular Dr. Tobias Kiesslich, Salzburg, Dr. Akiko Takahashi, 
Nagano, and Dr. Toshio Uraoka, Tokyo, and to the staff of Springer US, Clinical 
Medicine publishers, especially Andy Kwan and Richard Hruska, Senior Editor, 
Clinical Medicine. 
 The Editors 
 
xi
 Contents
Part I General Principles of Endoscopy for Early Gastrointestinal 
Neoplasias
 1 Endoscopic Screening and Surveillance: Indications 
and Standards. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Frieder Berr, Thierry Ponchon, and Tsuneo Oyama
 2 Histopathology of Early Mucosal Neoplasias: Morphologic 
Carcinogenesis in the GI Tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Daniel Neureiter and Tobias Kiesslich
 3 Principles of Endoscopic Resection: Diagnostic and 
Curative Resection of Mucosal Neoplasias . . . . . . . . . . . . . . . . . . . . . 35
Tsuneo Oyama and Naohisa Yahagi
 4 Endoscopic Detection and Analysis of Mucosal Neoplastic 
Lesions: Enhanced Imaging and Tumor Morphology . . . . . . . . . . . . 49
Frieder Berr, Toshio Uraoka, Thierry Ponchon, and Naohisa Yahagi
 5 High-Resolution Endoscopic Ultrasound: Clinical T-Staging 
of Mucosal Neoplasms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
Yuichiro Kuroki, Toshio Uraoka, and Gernot W. Wolkersdörfer
Part II Organ-Specifi c Endoscopic Analysis of Early Neoplasias
 6 Squamous Cell-Lined Esophagus and Hypopharynx: 
Mucosal Neoplasias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Tsuneo Oyama
 7 Columnar Epithelium-Lined (Barrett’s) Esophagus: 
Mucosal Neoplasias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
Ralf Kiesslich
xii
 8 Stomach: Mucosal Neoplasias. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
Tsuneo Oyama
 9 Duodenum and Small Bowel: Mucosal Neoplasias . . . . . . . . . . . . . . . 173
Thierry Ponchon
10 Colorectum: Mucosal Neoplasias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193
Frieder Berr, Toshio Uraoka, and Naohisa Yahagi
11 Chronic Infl ammatory Bowel Disease in Remission: 
Mucosal Neoplasias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241
Ralf Kiesslich
Appendix: Terminology (Proposed Throughout the Book) . . . . . . . . . . . . 261
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265 
Contents
xiii
 Contributors 
 Frieder Berr Department of Internal Medicine I , Paracelsus Medical 
University/Salzburger Landeskliniken , Salzburg , Austria 
 Ralf Kiesslich Department of Internal Medicine, Gastroenterology 
and Oncology , St. Marienkrankenhaus Frankfurt , Frankfurt am Main , Germany 
 Tobias Kiesslich Department of Internal Medicine I, Institute of Physiology 
and Pathophysiology , Paracelsus Medical University , Salzburg , Austria 
 Yuichiro Kuroki Department of Gastroenterology and Endoscopy Unit , 
 Toranomon Hospital , Minato-ku , Tokyo , Japan 
 Daniel Neureiter Institute of Pathology , Paracelsus Medical University/Salzburger 
Landeskliniken , Salzburg , Austria 
 Tsuneo Oyama Department of Endoscopy , Saku Central Hospital Advanced 
Care Center , Saku , Nagano , Japan 
 Thierry Ponchon Department of Digestive Diseases , Hôpital Eduard Herriot , 
 Lyon , France 
 Toshio Uraoka Department of Gastroenterology , Tokyo Medical Center , 
 Meguro-ku , Tokyo , Japan 
 Gernot W. Wolkersdörfer Department of Internal Medicine I , 
 Paracelsus Medical University/Salzburger Landeskliniken , Salzburg , Austria 
 Naohisa Yahagi Division of Research and Development for Minor Invasive 
Treatment, Cancer Center , Keio University School of Medicine , Shinjuku-ku , 
 Tokyo , Japan 
 Part I 
 General Principles of Endoscopy for 
Early Gastrointestinal Neoplasias 
3F. Berr et al. (eds.), Early Neoplasias of the Gastrointestinal Tract, 
DOI 10.1007/978-1-4614-8292-5_1, © Springer Science+Business Media New York 2014
1.1 Introduction 
 The gastrointestinal (GI) tract is the organ system bearing the highest cancer 
 incidence (1.0–1.4 × 10 3 ) and mortality (0.7–0.9 × 10 3 per 10 5 and year). Annual 
mortality- to-incidence ratio ranges from 42 % for colorectal cancer to 82 % for 
esophageal cancer and exceeds 66 % for gastric cancer in the West but has fallen 
below 40 % in Japan [ 1 , 2 ]. Curative radical surgery with complete removal of fi rst- 
and second-tier lymph nodes for early gastric cancer (≤pT1) achieved 5-year over-
all survival rates (OS) exceeding 90 % [ 3 , 4 ]. Endoscopic resection en bloc yielded 
comparable 5-year OS (92–93 % without mortality from cancer) for early gastric 
cancers selected according to the criteria of the Japanese Gastric Cancer Association 
or expanded criteria of National Cancer Center (NCC), Tokyo [ 5 , 6 ]. 
 Early GI cancers mostly (>95 %) show differentiated grading, except gastric 
cancer (in only ~60 %). Early cancer when differentiated (HGIN, G1, G2) pro-
gresses slower to systemic disease, e.g., within 3 years, than undifferentiated cancer 
[ 3 ]. This allows some time for detection of early cancer – as necessary for screening 
and surveillance programs. 
 Chapter 1 
 Endoscopic Screening and Surveillance: 
Indications and Standards 
 Frieder Berr , Thierry Ponchon , and Tsuneo Oyama 
 F. Berr (*) 
 Department of Internal Medicine I , Paracelsus Medical University/Salzburger Landeskliniken , 
 Muellner Hauptstrasse 48 , 5020 Salzburg , Austria 
 e-mail: frieder.berr@pmu.ac.at 
 T. Ponchon 
 Department of Digestive Diseases , Hôpital Eduard Herriot, Pavillon H, Place d’Arsonval , 
 69437 Lyon , France 
 T. Oyama 
 Department of Endoscopy, Saku Central Hospital Advanced Care Center , 
 3400-28 Nakagomi , Saku, Nagano 3850051 , Japan 
4
1.2 Rationale for Endoscopic Screening and Surveillance 
 Detection of precursors or cancer in early stage (pT1a, differentiated grade) is 
critical to reduce mortality from gastrointestinal cancers. Endoscopy is best for 
detection of early GI cancer and precursor lesions, much better than fecal screen-
ing for occult blood loss or attempts of serum screening tests [ 7 – 10 ]. Endoscopic 
screening of the population aims to reduce mortality from frequent GI cancers. 
Beyond the average risk of GI cancers in the general population, there are many 
individuals with high-risk profi le depending on environmental factors (e.g., car-
cinogen exposure, smoking, alcohol abuse) or/and individual disposition (familial 
inheritance, chronic GI infl ammatory diseases). Such individuals require opportu-
nistic screening endoscopy earlier in life and surveillance at more frequent inter-
vals than the general population [ 8 , 10 – 14 ]. However, even in specialty practice up 
to 39 % of patients had CRC screening without taking the risk profi le and family 
history, and 55 % of patients with strong family history had received inappropriate 
screening and surveillance [ 11 ]. And after complete resection of early cancer or 
precursor lesion, the interval for follow-up endoscopy depends on the risk for 
recurrence [ 8 – 10 ]. 
 Note 
 Taking the history of carcinogenic risk factors including family history is a prereq-
uisite for any screening endoscopy as well as for schedulingfollow-up examina-
tions (endoscopic surveillance). 
 Colorectal cancer (CRC) is the third most common cause of cancer-related death 
worldwide ranking second in Western countries and third in Japan [ 15 ], with similar 
yearly incidence rates (cases/100,000/year) in the USA (range 28–38), Western 
Europe (33–50), and Japan (22–58) [ 1 , 7 , 15 , 16 ]. In the US National Polyp Study, 
the incidence rate of CRC was much lower after clearing colonoscopy (with resec-
tion of all neoplasias) than predicted from the US population [ 14 ]. This delivered 
the rationale for nationwide colonoscopy screening programs in many countries, to 
reduce mortality from CRC. 
 Gastric cancer is frequent in Japan (incidence ~25/100,000/year) justifying 
screening of the general population [ 15 , 16 ]. Screening endoscopy is recommended 
to start at the age of 40 years and has decreased cancer-related mortality [ 17 – 19 ]. 
The incidence of gastric cancer (GC) also is high in China, Chile, and Eastern Europe 
[ 1 , 16 , 17 , 20 ]. However, in most Western countries, GC is too rare (e.g., ≤5/100,000/
year in the USA) to start an endoscopic screening program [ 1 , 12 , 16 ]. Nowadays, 
the epidemiology of gastrointestinal cancers is becoming more similar in Japan and 
Western countries because of a global trend for similar lifestyle and nutrition, rising 
prevalence of chronic gastroesophageal refl ux disease, and rapidly declining preva-
lence of Helicobacter pylori infection. In Western countries, evidence can be claimed 
F. Berr et al.
5
for endoscopic surveillance of Barrett’s esophagus to detect early malignancies [ 12 ]. 
As endoscopic screening and surveillance for GI cancers is an evolving topic, we 
emphasize to refer to your national guidelines. 
1.2.1 Screening Colonoscopy for Prevention of CRC 
1.2.1.1 Colonoscopy 
 Colonoscopy performed in due quality is the best diagnostic standard for detection 
of neoplasias in the entire colon [ 8 , 10 , 17 ] – and combined with polypectomy of all 
detected adenomas (clearing colonoscopy) reduces the risk of colon cancer by 
66–71 % for 10 years after colonoscopy [ 14 ]. Annual fecal occult blood test (FOBT) 
screening reduced this risk by 23 %, because one-third of participants received colo-
noscopy (and polypectomy of neoplasias) [ 21 ]. The risk of complications of screen-
ing colonoscopy is low (overall 0.39 % for diagnostic, 1.02 % for therapeutic 
screening colonoscopy; mortality 1:150,000) [ 10 , 22 , 23 ]. 
 Note 
 Recommendations for asymptomatic, average-risk individuals:
 Age ≥50 years [≥40 years in Japan] → screening colonoscopy (every 10 years) 
 [Aim: prevention and early detection of colon cancer] 
 If not → annual FOBT → colonoscopy, if FOBT is positive 
 [Aim: (early) detection of asymptomatic colon cancer] [ 10 , 23 ] 
1.2.2 Individuals with Increased Risk for Colorectal Cancer 
 Approximately 75 % of CRC occur sporadically in average-risk individuals and up 
to 25 % in persons with positive family history (FH) for colon adenomas or cancer, 
i.e., increased risk profi le [ 8 , 10 , 17 ]. Monogenic autosomal dominant inherited 
familial cancer syndromes account for less than 10 % of all CRC – familial adeno-
matous polyposis coli (FAP) for 1 % and hereditary nonpolyposis colon cancer 
(HNPCC) for 5 % – and another 15–20 % of all CRC cases report colon cancer or 
adenomas in the family history (FH) [ 24 ]. The lifetime risk for CRC ranges from 60 
to 80 % with HNPCC and is up to nearly 100 % with classical FAP [>100 colon 
adenomas] by age 40–50 years, and the onset is at young age [ 13 , 25 ] (Fig. 1.1 ). 
Attenuated FAP (with less adenomas [10–99] and later onset) is suggested by the 
following criteria: (a) at least 2 FDRs with 10–99 adenomas at the age >30 years 
(none under age 30 years) or (b) one FDR with 10–99 adenomas and one FDR with 
1 Endoscopic Screening and Surveillance: Indications and Standards
6
CRC and few adenomas. There is a 25 % chance of identifying an APC mutation in 
this attenuated FAP syndrome [ 13 ]. A very rare form of adenomatosis coli (10–>100 
adenomas) manifested before the age of 30 years is MAP (MUTYH-associated 
adenomatous polyposis), an autosomal recessive disorder due to biallelic MUTYH 
mutations. MAP persons show predilection of CRC in the right colon as well as 
adenomas and cancer in the duodenum [ 13 ]. Peutz-Jeghers syndrome (PJS) and 
familial juvenile polyposis (FJP) have a lifetime risk of CRC up to 39 % and 20 %, 
respectively [ 26 , 27 ]. Chronic infl ammation also increases the probability of cancer, 
the risk for ulcerative colitis is 7–15 % after 20 years – even higher when combined 
with primary sclerosing cholangitis – and it is similar for Crohn’s colitis [ 28 , 29 ]. 
Table 1.1 lists increased risk conditions for CRC.
1.2.2.1 Screening with Positive Family History 
 The lifetime risk for colon cancer is about 1 % in individuals without increased 
risk factors and 2 % in individuals with fi rst-degree relatives (FDRs) with colonic 
Cu
m
u
la
tiv
e
 
in
ci
de
nc
e 
(%
)
20
20
40
60
80
100
40
age [years]
Sporadic
pos. family history
HNPCC
FAP
60
(CRC/adenoma
in 1 FDR <60 year)
 Fig. 1.1 Cumulative 
incidence of CRC by age in 
different risk groups: FDR, 
fi rst degree relative; HNPCC, 
hereditary non-polyposis coli 
cancer; FAP, familial 
adenomatous polyposis coli 
(Modifi ed acc. to Winawer 
et al. [ 23 ]) (Permission 
granted by AGA Institute, 
W.B. Saunders Comp) 
 Table 1.1 Individuals with increased risk for CRC 
 Condition Reference 
 Family history (FH) of colon adenoma or carcinoma [ 25 , 30 ] 
 Hereditary colorectal carcinomas (rapid progression adenoma → carcinoma) 
 HNPCC, autosomal dominant [ 24 , 26 ] 
 FAP, autosomal dominant [ 10 , 24 ] 
 MAP (MUTYH-associated adenomatous polyposis), autosomal recessive [ 10 , 24 ] 
 Peutz-Jeghers syndrome (PJS) [ 26 , 27 ] 
 Familial juvenile (hamartomatous) polyposis (FJP) [ 26 ] 
 Chronic infl ammatory bowel disease (UC, Crohn’s colitis) [ 28 , 29 ] 
 Surveillance after polypectomy or surgery for CRC See [ 10 , 24 ] 
 
F. Berr et al.
7
 Table 1.2 Clinical criteria for microsatellite instability (MSI) genetic testing (for HNPCC) [ 13 ] 
 Amsterdam criteria II Revised Bethesda guidelines 
 At least 3 relatives with CRC or a Lynch 
syndrome- associated cancer a occurring 
in the following combinations: 
 One CRC diagnosed at age <50 years 
 One is fi rst-degree relative to others MSI-H-positive CRC at age <60 years 
 In at least two successive generations Syn-/metachronous Lynch syndrome- associated 
tumors a 
 At least one diagnosed at age <50 years 1 CRC and 1 FDR with Lynch syndrome- associated 
tumor a , 1 at age < 50 years 
 FAP excluded in the CRC cases 1 CRC with two or more FDR or SDR with a Lynch 
syndrome-associated tumor a 
 Tumors verifi ed by histopathology 
 
a
 These include colorectal, endometrial, stomach, ovarian, pancreas, ureter, renal pelvis, biliary tract, 
and brain tumors, sebaceous gland adenomas, keratoacanthomas, and carcinoma of the small bowel 
 Table 1.3 Recommended screening colonoscopy for high risk of CRC [ 10 , 24 , 26 , 31 ] 
 Risk factors 
 Screening colonoscopies 
 Age at begin Intervals (years) 
 Positive FH only 
 1. One SDR or TDR (cousin) with CRC 50 years 10 
 2. One FDR with CRC/adenoma >60 years or 
>two SDR with CRC 
 40 years 10 
 One FDR with CRC/adenoma <60 years 40 years or 10 years before 
manifestation in FDR 
 5 
 Monogenic hereditary syndromes 
 3. FAP (classical form) 12 years 1 or 2 
 Attenuated FAP (10–100 adenomas) 25 years, or 10 years before 
CRCin FDR 
 1 or 2 
 4. HNPCC 20 or 25 years, or 10 years 
before earliest CRC in FDR 
 1 or 2 
 5. Peutz-Jeghers syndrome (PJS) 18 years 2 
 6. Familial juvenile polyposis (>10 polyps) 12 years 3–5 
 Chronic infl ammation 
 7. Ulcerative colitis, Crohn’s colitis Pan-/colitis for 8–10 years 2 (−1) 
 See Chap. 11 for surveillance of ulcerative colitis and Crohn’s colitis 
adenoma or carcinoma at age <60 years (i.e., positive family history FH), and it is 
3.5–4 % when one FDR had colon cancer at age <50 years or more than 1 FDR had 
colon cancer or when two or more second-degree relatives (SDR) had colon cancer 
[ 25 ] (Fig. 1.1 ). The risk for colon cancer is only marginally increased (~1.5–1.8- 
fold) when one FDR at age >60 years or one SDR had colon adenoma or cancer 
[ 25 ]. In cases of positive FH and more so in cases with strong hereditary risk for 
CRC (e.g., positive Amsterdam criteria, Table 1.2 ) the risk rises earlier in life and 
becomes very high in the cancer syndromes, e.g., ~60 % in HNPCC and 80–90 % 
in FAP at age of 60 years (Fig. 1.1 ) [ 8 , 13 , 23 ]. Recommendations for surveillance 
are listed in Table 1.3 .
1 Endoscopic Screening and Surveillance: Indications and Standards
8
1.2.2.2 Genetic Testing 
 Genetic testing for specifi c mutations (APC gene, mismatch repair (MMR) genes) 
is recommended for:
 FAP of the colon (→ sequencing of APC gene) 
 Presence of criteria compatible with HNPCC (compare Table 1.2 ) 
 Cases with very-high-risk FH require genetic testing of the carcinoma (if MSI 
positive) of the index patient fi rst by immunohistochemistry for MMR proteins, 
followed by sequencing the gene of an unexpressed MMR protein to detect the 
specifi c MMR gene mutation. Consecutively, family members at risk must be 
screened for this MMR gene mutation by a center for genetic studies [ 10 ]. Carriers 
of the mutation need surveillance for CRC and related cancers. 
 Note 
 Up to 20 % of FAP cases have negative FH (probably new germline FAP mutations 
or biallelic autosomal recessive MUTYH gene mutations). Likely hereditary cancer 
syndromes must be evaluated in collaboration with a center for genetic diseases. 
Sub-/total colectomy with ileorectal anastomosis or even ileoanal pouch may be 
indicated for FAP, for HNPCC, and rarely for ulcerative colitis [ 10 , 13 , 24 ]. 
1.3 Gastric Cancer 
 Gastric cancer (GC) is the second leading cause of cancer-related death worldwide, 
and the 4th in the USA and Western Europe. The incidence rates for gastric cancer 
(GC) have decreased by 75–85 % during the past 60 years to 3–5/100,000/year in 
the USA and Western Europe but remain higher in Japan (fi vefold), China, Chile, 
and Eastern Europe [ 1 , 16 – 18 ]. Radiographic and endoscopic screening has 
decreased GC-specifi c mortality in Japan [ 18 , 19 , 32 ]. In Western countries, oppor-
tunistic screening and surveillance endoscopy only is common. 
1.3.1 Increased Risk for Gastric Cancer 
 The two main types are “intestinal type,” forming gland-like tubular structures, and 
“diffuse type” lacking cell cohesion and infi ltrating the wall by spreading of single 
cells. The intestinal type is easier to detect at endoscopy and spreads slower. 
The following disorders are considered for surveillance gastroscopy (see Table 1.4 ). 
The precursor lesions for intestinal-type GC are severe chronic atrophic gastritis 
(autoimmune type A or Helicobacter pylori -induced type B) with intestinal metaplasia 
(IM) or biliary refl ux-induced chronic remnant gastritis after partial gastrectomy 
[ 12 , 18 , 19 ]. Intestinal metaplasia with HGIN has a 33–85 % chance of GC [ 12 ]. 
F. Berr et al.
9
Families with autosomal dominant diffuse-type GC require genetic diagnosis and 
prophylactic gastrectomy [ 33 ], because the effi ciency of surveillance is unproven 
for diffuse-type GC which is poorly detectable.
1.3.2 Esophageal Squamous Cell Cancer 
 Cancer of the squamous cell epithelium of the esophagus is relatively rare with inci-
dence rates of 1.5–5 per 100,000 and year in most countries, except for a few high-
prevalence areas such as Hunyuan county/China, Singapore, and Iran (incidence 
rates up to 140/10 5 /year) [ 1 , 12 , 34 ]. Therefore, endoscopic screening is not indicated 
in general, but index endoscopy and surveillance is recommended for some groups 
with high risk for SCC [ 12 , 35 , 36 ]. 
 Evidence for inheritance of esophageal cancer is lacking, although familial 
clustering has rarely been reported for SCC as well as Barrett’s esophagus [ 34 ]. 
1.3.2.1 Risk Groups for Esophageal SCC 
 The risk of esophageal SCC is increased in men (4-fold vs women), in particu-
lar with chronic heavy smoking and alcohol abuse (approx. 25-fold) [ 34 , 35 ]. 
 Table 1.4 Individuals with increased risk for gastric cancer [ 12 , 18 – 20 , 33 ] 
 High risk for 
 Surveillance endoscopy [ 12 ] 
 Onset at years Intervals (years) 
 (a) Intestinal-type GC 
 1. Atrophic gastritis type B with IM a 
(H.p. pos.) 
 Index endoscopy → H.p. eradication 
 Polypoid-type chronic gastritis with IM a Individualize Unknown 
 2. Chronic autoimmune gastritis type A 
with IM a 
 Index endoscopy Unknown 
 3. Gastric intestinal metaplasia (IM a ) Check at 3 months with 
mapping and biopsies 
 3 months–1 year 
 IM a and low-grade IEN 
 IM a and high-grade IEN Confi rm → ESD or surgery ½–1 year 
 4. Partial Billroth II gastrectomy Index endoscopy → H.p. eradication 
 (Chronic bile refl ux gastritis) 15 years after PGE 2–3 years 
 5. Gastric adenoma (35 % malignant 
foci, [ 17 ]) 
 EMR or ESD 1–3 years 
 6. FAP (gastro-/duodenoscopy) and 
HNPCC [ 12 ] 
 Index endoscopy and 
individualize 
 6 months–3 years 
 (b) Diffuse-type GC 
 5. Hereditary diffuse GC (30 % CDH1 
mutation) 
 Genetic diagnosis [ 33 ] Prophylactic 
gastrectomy 
 Recommendations of the ASGE [ 12 ] 
 
a
 IM intestinal metaplasia 
1 Endoscopic Screening and Surveillance: Indications and Standards
10
The latter group may undergo surveillance endoscopy starting at the age of 50 years – 
without proven evidence [ 12 ]. In addition, some cancers of the upper GI tract are 
strongly associated. Head-and-neck SCC exhibits an ~20 % risk of syn- or metachro-
nous esophageal SCC [ 36 ] and the latter an ~10 % risk of metachronous intestinal-
type gastric cancer. About 10 % of oropharyngeal SCC show syn- or metachronous 
SCC in the esophagus [ 37 , 38 ]. Patients treated for these carcinomas need surveil-
lance endoscopies of the oro- and hypopharynx, esophagus, and stomach. 
 Diseases with increased risk of esophageal SCC are prolonged esophageal muco-
sal damage caused by achalasia and status post lye injury or chronic caustic injury, 
e.g., caused by hot beverages [ 39 , 40 ]. Some hereditary diseases of squamous epi-
thelium have a high risk of esophageal cancer such as tylosis with palmar and plan-
tar hyperkeratosis [ 41 ]. Defi ciency of zinc, selenium, or folate and endemic human 
papilloma virus infection of the esophagus may increase the risk of esophageal SCC 
[ 36 , 42 – 44 ]. High-risk groups for SCC justifying surveillance endoscopies every 
1–3 years are listed in Table 1.5 .
1.3.3 Adenocarcinoma of the Esophagus or Gastroesophageal 
Junction (GEJ) 
 Since 40 years the incidence of previously rare adenocarcinoma (AC) of the esopha-
gus and the gastroesophageal junction has rapidly increased, and this AC is now the 
prevailing type of esophageal cancer in the USA and Western Europe [ 1 , 45 , 47 ]. 
Nearly all of these AC arise from Barrett’s epithelium, i.e., columnar-lined 
 Table 1.5 Individuals with high risk of esophageal cancer [ 12 , 35 , 37 – 41 , 44 – 46 ] 
 High risk forSurveillance endoscopy [ 12 , 45 ] 
 Recommended onset Intervals (years) 
 Esophageal SCC 
 Aerodigestive tract SCC (head and neck ~, lung ~) One index endoscopy Unknown 
 Syn-/metachronous esophageal SCC (in 10 % of 
patients) 
 Individualize Unknown 
 Gastric cancer (risk of double cancer) One index endoscopy Unknown 
 Achalasia (16-fold↑ risk after ~14 years) 15 years after onset Unknown 
 Strictures from lye, radiation of caustic injury 10–15 years after injury 1–3 
 Partial gastrectomy (PGE) (chronic bile refl ux 
esophagitis) 
 15 years after PGE 2–3 
 Hereditary diseases of the squamous epithelium, 
e.g., tylosis 
 At age 30 years 1–3 
 Papillomavirus infection (High-risk immigrant) Unknown 
 Adenocarcinoma of the esophagus or GEJ 
 Barrett’s esophagus in GERD See Chap. 7 
 Alcohol and smoking Index endoscopy Individualize 
 Obesity (abdominal type) – Unknown 
F. Berr et al.
11
epithelium without or with intestinal metaplasia [ 47 , 48 ]. The underlying cause for 
transformation to Barrett’s epithelium is chronic gastroesophageal refl ux disease 
(GERD) [ 49 ], which is favored by abdominal-type obesity, hiatal hernia, and 
Western diet high in calories, fat, and animal meat and low in fi ber [ 45 , 47 ]. The role 
of gastric infection with Helicobacter pylori is controversial for AC. Chronic 
gastroesophageal refl ux disease is the most important risk factor, next to chronic 
alcohol ingestion and smoking [ 50 ]. 
1.4 Standards for Screening and Surveillance Endoscopy 
 Detection of small (<10 mm) and minute (<5 mm) neoplastic lesions during screening 
or surveillance endoscopy depends on (a) proper cleaning and preparation of the 
organs, (b) examination technique and endoscopic equipment, and (c) experience 
and alertness of the examiner. To assure outcome quality of these diagnostic proce-
dures, published benchmark criteria (see below) should be monitored, evaluated, 
and achieved in every endoscopy unit. 
 General aspects to document for endoscopy are [ 51 ]:
 I. Pre - procedure 
 (a) Proper indication including justifi cation of nonstandard indications 
 (b) Proper consent (risks in Table 1.6 ), including documentation of 
anticoagulation
 (c) Pre-procedure history and physical examination for risk stratifi cation 
 (d) Level of desired sedation 
 II. Intra - procedure 
 (e) Patient monitoring with documentation of vital parameters and medications 
 (f) Image documentation of endoscopic landmarks and abnormalities 
 III. Postprocedure 
 (g) Discharge letter (endoscopy procedure report) and documentation 
 (h) Patient instructions (→ sedation and potential postprocedure complica-
tions) 
 (i) Pathology follow-up and report 
 (j) Record keeping of adverse events and complications of the endoscopy unit 
 (k) Communication with patient (patient satisfaction) and referring physician 
 (l) Anticoagulation plan 
 Table 1.6 Risks of 
diagnostic colonoscopy [ 8 , 9 , 
 51 ] 
 Complication Risk 
 Bleeding 0.01 % (after snare polypectomy 0.8 %) 
 Perforation 0.01 % (after snare polypectomy 0.06 %) 
 Mortality 2/>300,000 colonoscopies 
1 Endoscopic Screening and Surveillance: Indications and Standards
12
1.4.1 Colonoscopy 
 Approximately 8 % of patients with newly diagnosed colorectal carcinoma had a 
negative colonoscopy within the past 5 years [ 52 ]. Likely causes for missed detection 
of pre-/malignant lesions are a miss rate for detectable adenomas (~11 % when 
5–10 mm size) and tiny fl at adenomas or carcinomas of <5 mm size [ 52 ]. 
1.4.1.1 Bowel Preparation 
 Bowel preparation is essential for diagnostic outcome. Oral intake of iron medications 
(causing discoloration of mucosa) and fruit or bread with small seeds should be 
discontinued for a few days. Standard preparation is performed orally by intake of 
sodium picosulfate solution (10 ml) to empty the rectum and subsequently intake of 
2–3 l of polyethylene glycol-sodium sulfate solution (PEG-ELS) within 60–90 min 
the evening before and/ or early in the morning 3–4 h before examination. We rec-
ommend to add 5 ml of dimethicone solution [Gascon] per liter of PEG solution to 
remove mucus from colonic mucosa. The interval between last oral fl uid intake and 
colonoscopy shall be 3 h to ensure gastric emptying before sedation. We recom-
mend checking the quality of preparation (i.e., discharge of yellowish stool fl uids 
without solids) before settling the patient. 
1.4.1.2 Examination 
 Colonoscopes equipped with NBI and at least 50-fold magnifying capacity should be 
used and colonoscopy performed as one-examiner method with loop-less insertion 
technique [ 53 ]. Use sedation (e.g., midazolam 0.7 mg/kg b. wt.) or propofol intrave-
nous anesthesia according to national guidelines. Completeness of colonoscopy must 
be documented by images of the cecal end and mound of the appendix and – as 
proof – ileal intubation with imaging. An antispasmodic (butylscopolamine 10–20 mg) 
is administered intravenously (or glucagon 1 mg i.v. in case of glaucoma or frank 
prostatic hypertrophy) prior to withdrawal of the scope. To scrutinize the entire muco-
sal surface including proximal sides of haustral folds withdrawal time will last at least 
6 min, quality indicators for screening colonoscopy should be recorded for all 
examinations on the basis per examiner and per endoscopy unit – and should meet 
benchmark indicators (Table 1.7 ).
 Table 1.7 Benchmark indicators for quality of colonoscopy [ 8 , 9 , 48 , 51 , 52 ] 
 Quality indicator Parameter 
 Cecal intubation rate >95 % for screening of healthy adults (>97 %) 
 >90 % of all cases (photodocumentation) 
 Adenoma detection rate >25 % of colonoscopies in >50-year-old men 
 >15 % of colonoscopies in >50-year-old women 
 Withdrawal time >6 min (screening of healthy adults; documented) 
F. Berr et al.
13
 The endoscopist must maintain focussed attention for:
 Small/minute superfi cial-type lesions (0-IIb, 0-IIc) 
 Minute alterations in color (reddish or pale spots) or surface structure 
 Spots with interrupted submucosal or irregular mucosal vascular pattern 
 Changes in surface outline of walls or haustral folds during in-/de-suffl ation 
 Spots with contact bleeding 
 Such fi ndings must be analyzed by image-enhanced endoscopy (see Chap. 10 ). 
1.4.2 Upper Gastrointestinal Endoscopy 
 Upper GI endoscopy for detection of neoplasias should be performed 10–20 min 
after oral intake of a glass of water with proteinase or acetylcysteine (see below), to 
clean the mucosa from mucus (compare Fig. 1.2a, b ), and under deep intravenous 
sedation complying with national guidelines. 
a
b
 Fig. 1.2 ( a ) Gastric body 
cleaned with proteinase 
pretreatment and washing 
using a water jet. ( b ) Gastric 
body without proteinase 
pretreatment. In spite of 
water-jet rinsing of the 
mucosa, adherent mucin 
forms a foamy gel on gastric 
mucosal folds severely 
impairing assessment of 
epithelial surface structure 
(Reprinted from Oyama [ 54 ], 
permission granted by 
Nankodo Co., Ltd.) 
 
1 Endoscopic Screening and Surveillance: Indications and Standards
14
 Note 
 In order to clean gastric mucosa from mucus, the patient drinks a glass of water 
containing dimethicone and proteinase (0.25 g Pronase®/25 mL water, Kaken 
Seiyaku Corp., Tokyo) 10 min before endoscopy. An alternative mixture is 25 ml 
of water with 400 mg N-acetylcysteine and 20 mg activated dimethicone (all con-
stituents pharmaceutical grade). Copious rinsing of mucosa with water jet is essen-
tial for endoscopic assessment of mucus-devoid gastric surfaceand capillary 
pattern [ 54 ]. 
 High-resolution video endoscopes with magnifying virtual chromoendoscopy 
(i.e., NBI, FICE, i-scan) must become standard equipment that supports sensitive 
detection and accurate diagnosis of mucosal lesions. In general, detection of small 
and minute neoplastic lesions depends on examiner capability as well as quality of 
endoscopic equipment. The examination should follow a standardized screening 
approach for gastroesophageal neoplasias, and fi ndings must be documented by 
multiple pictures showing location and size of any lesion as well as structural detail 
on magnifi cation in WLI and NBI or CE. For precise description of the localization 
of any lesion in the esophagus, straighten the tube of the endoscope and look for the 
notch of the left main bronchus (25–28 cm from incisor teeth and between 10 and 
12 on a clockface) corresponding to the ventral side. 
 The ASGE has defi ned quality requirements for surveillance gastroscopy in 
Barrett’s esophagus (BE) or cases with gastric ulcers as follows [ 12 , 45 ].
 (a) Measuring of the length of BE in cm from incisors (p.i.) by location of GE junc-
tion and squamocolumnar junction and classifying according to the Prague 
classifi cation (comp. Chap. 7 ). 
 (b) “An adequate number of biopsies” must be taken in all cases of suspected BE, 
according to the Seattle protocol after image enhancement by NBI or staining 
(e.g., with acetic acid). 
 (c) Protocol biopsies from all four quadrants every 2 cm for known Barrett’s 
esophagus and in addition targeted biopsies from suspected neoplastic lesions 
and four quadrant biopsies every 1 cm in case of Barrett’s esophagus with 
known dysplasias in that area. 
 (d) Biopsy specimens are taken from gastric ulcers [ 12 , 17 ]. 
 Diagnostic strategies of early Barrett’s esophageal cancer in Japan recom-
mend magnifying (>60-fold) endoscopic analysis of lesions (similar as for early 
gastric cancer) and diagnosis by targeted biopsies [ 55 ]. Protocols of esophago-
gastroduodenoscopy for early cancer screening are more explicit in Japan than in 
Western countries. For basic technique, skill training, and systematic observa-
tion, we recommend the pocket guide for GI endoscopy by Arakawa [ 56 ]. 
Recommendations for detection and analysis of neoplasias are given in Chaps. 4 , 
 6 , 7 , 8 , 9 , 10 and 11 . 
 The washout period of anticoagulants prior to biopsy is given in Table 1.8 .
F. Berr et al.
15
1.4.2.1 Antibiotic Prophylaxis 
 Antibiotic prophylaxis is not required for upper or lower GI endoscopy, unless the 
patient is severely immune compromised, has cardiac valvular replacement or disease, 
or undergoes a procedure with high infective risk (e.g., ERC for cholangitis, placement 
of PEG, EUS-FNA of cystic GI lesions, ligation of esophageal varices). For these con-
stellations, 30–60 min prior to endoscopy a single i.v. dose is recommended (depend-
ing on patient drug tolerance): amoxicillin 2 g i.v. or cefazolin 1 g i.v. or ciprofl oxacin 
500 mg i.v. [ 58 ]. There are no such recommendations for ESD, but high-risk individu-
als should receive antibiotic prophylaxis before esophagogastric or colonic ESD. 
 Acknowledgments The authors gratefully acknowledge Toshio Uroaka MD for critical discussion 
and improvements in the manuscript of this chapter. 
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1 Endoscopic Screening and Surveillance: Indications and Standards
19F. Berr et al. (eds.), Early Neoplasias of the Gastrointestinal Tract, 
DOI 10.1007/978-1-4614-8292-5_2, © Springer Science+Business Media New York 2014
2.1 Introduction 
 Early cancer suggests carcinoma curable with resection – a clinical concept coined 
in Japan – and more and more defi ned by macroscopic and microscopic criteria over 
the years throughout the gastrointestinal tract [ 1 – 3 ]. In general, it is applied to 
mucosal cancers without or with minor submucosal invasion, with a low probability 
of lymph node metastasis and >90 % rate of cure by R0 resection. 
 In Japanese tradition, endoscopic features have been correlated with histopathologi-
cal fi ndings. Mucosal surface alterations of well-differentiated cancers and precursor 
lesions as compared to non-neoplastic mucosa have been characterised by histology in 
parallel with stereomicroscopic observation and image-enhanced endoscopy (IEE). 
Well-differentiated early mucosal neoplasias, e.g. in the colon, revealed distinct 
margins and typical alterations of epithelial surface and mucosal capillary structure 
[ 4 , 5 ]. In addition, several morphological pathways of carcinogenesis exist in each 
organ such as colon, stomach, or oesophagus [ 4 , 6 – 9 ], and therefore, the endoscopist 
must be familiar with different early cancerous lesions and their precursors. 
 Western and Japanese classifi cations differed in the criteria for intraepithelial 
high-grade dysplasia vs. mucosal cancer [ 10 , 11 ]. This has been largely resolved by 
the consensus Vienna classifi cation of gastrointestinal epithelial neoplasias [ 12 ] 
extended in Paris by the macroscopic and microscopic International Classifi cation 
which is based on Japanese criteria [ 6 ]. Early cancers and precursor lesions in the 
gastrointestinal tract are best defi ned with these classifi cations. 
 Chapter 2 
 Histopathology of Early Mucosal Neoplasias: 
Morphologic Carcinogenesis in the GI Tract 
 Daniel Neureiter and Tobias Kiesslich 
 D. Neureiter (*) 
 Institute of Pathology , Paracelsus Medical University, 
 Muellner Hauptstrasse 48 , Salzburg 5020 , Austria 
 e-mail: d.neureiter@salk.at 
 T. Kiesslich 
 Department of Internal Medicine I, Institute of Physiology and Pathophysiology , Paracelsus 
Medical University , Muellner Hauptstrasse 48 , Salzburg 5020 , Austria 
20
2.1.1 Paris Classifi cation and Malignant 
Potential of Neoplasms 
2.1.1.1 Classifi cation of Malignant Mucosal Neoplasms 
 The International Classifi cation (for macroscopic types, see Fig. 4.4 ) is based on the 
histopathological defi nitions agreed upon in the Vienna classifi cation (Table 2.1 ). 
There is still some disagreement between Japanese and Western pathologists as to the 
categorisation of lesions into high-grade intraepithelial neoplasias (HGIN) or defi -
nite cancer in situ (T0m1), because diagnostic criteria of cancer are based more on 
biopsy-proven tumour invasion into the lamina propria of the mucosa in the West, but 
more on atypias (nuclear features and intraepithelial gland structure) similar to the 
intraepithelial spreading component of invasive carcinomas in Japan (Table 2.2 ). 
Therefore, up to 50 % of carcinomas in situ diagnosed in Japan may be categorised 
HGIN in the West [ 10 , 11 ]. However, Japanese pathologists better predicted from 
single biopsies the correct categorisation of the entire en bloc resected neoplasias, 
because the majority of HGIN in the stomach were defi nite cancers in the resected 
specimens [ 11 ]. For the decision whether an early malignant lesion should be 
resected en bloc, this difference is irrelevant, since both HGIN and carcinoma in situ 
should be removed en bloc [ 1 , 3 , 6 ]. Minor differences may also exist in the categori-
sation of low- vs. high-grade intraepithelial neoplasias (LGIN vs. HGIN), but this 
decision is primarily a matter of individual expertise and should involve an expert 
reference pathologist [ 3 , 6 , 10 ].
 Table 2.1 Vienna classifi cation of gastrointestinal epithelial neoplasia [ 12 ] 
 Category Description Japanese viewpoint 
 Category 1 Negative for neoplasia/dysplasia a 
 Category 2 Indefi nite for neoplasia/dysplasia a 
 Category 3 Non-invasive low-grade neoplasia (low-grade adenoma/dysplasia) a 
 Category 4 Non-invasive high-grade neoplasia 
 4.1 High-grade adenoma/dysplasia 
 
 Non-invasive 
carcinoma c 
 4.2 Non-invasive carcinoma (carcinoma in situ) b 
 4.3 Suspicion of invasive carcinoma a 
 Category 5 Invasive neoplasia 
 5.1 Intramucosal carcinoma d a 
 5.2 Submucosal carcinoma or beyond a 
 
a
 Identical 
 
b
 Non-invasive indicates the absence of evident invasion 
 
c
 High-grade adenoma/dysplasia could be regarded as non-invasive carcinoma according the 
Japanese criteria of atypia 
 
d
 Intramucosal indicates invasion into the lamina propria or muscularis mucosae. 
D. Neureiter and T. Kiesslich
21
2.1.1.2 Malignant Potential 
 The likelihood of nodal metastasis mainly depends on histologic grading and depth 
of submucosal invasion of any T1 carcinoma as well as on macroscopic type and 
 anatomical localisation in the gastrointestinal tract. 
 Well-differentiated mucosal cancer shows a relatively structured and continuous 
infi ltrative growth pattern of glandular crowding, branching, and budding with clear 
histologic borders to normal localised tissue being refl ected by clear endoscopic mar-
gins of the neoplasia. Relative loss of polar structure of epithelial cell layers, enhanced 
nucleus/cytoplasm ratio, and bulky growth of epithelial cell layer in the neoplasm 
(as compared to normal epithelium and mucosa) alter the surface aspect of mucosal 
neoplasias – inducing a mucosal pattern most often visible on IEE. In case of massive 
submucosal invasion of coherently growing carcinoma, the surface gland structure 
(typical for differentiated mucosal cancer) becomes destroyed – yielding highly irreg-
ular or even non-structured surface (amorphous pattern) on stereomicroscopic obser-
vation as well as on IEE. In addition, differentiated mucosal cancers require 
neoangiogenesis for deep submucosal invasion – showing on IEE irregular microves-
sels in mucosal proper layer as demonstrated by immunohistochemistry in resected 
early cancers and correlated with imaging features on IEE [ 1 , 3 , 5 , 14 ]. 
 Likelihood of lymph node metastasis generally increases with depth of invasion 
of well-differentiated early cancer [ 2 , 3 , 15 ]. The best data on these correlations 
have been collected in large surgical series of resected early cancers with dissection 
of regional lymph nodes [ 2 , 15 – 21 ], as summarised in Table 2.3 . To predict risk 
of metastasis to locoregional lymph nodes for well-differentiated early cancers, T1 
lesions of the colon are categorised into “low risk”, i.e. grading G1 or G2, no inva-
sion of lymphatic vessels (L0) or submucosal veins (V0), and submucosal extension 
of less than 1,000 μm, vs. “high risk” in the presence of any feature like tumour 
budding (isolated tumour cells at the invasive tumour front), submucosal invasion 
≥1,000 μm, lymphatic or venous vascular invasion, or grading G3 or G4 [ 15 ].
 Table 2.2 Japanese criteria for diagnosis of colorectal adenomas and differentiated cancers [ 13 ] 
 Criteria of atypia Normal Adenoma 
 Well-differentiated adenocarcinoma 
 Low grade High grade 
 Cellular 
atypia 
 Nuclear size (μm) 4.5 × 1.5 
 
 ≤20 × 10 
 Chromatin 
(blue-violet) 
 Dotted 
 
 Coarse, bright 
 Nuclear polarity Basal 
 
 Nonpolarised 
 Nucleus/gland 
ratio 
 Low 
 
 High 
 Nucleus/cell ratio 0.15–0.3 
 
 0.5–0.9 
 Structural 
atypia 
 Glandular 
structure 
 Tubular Tubular/villous 
± branching 
 Tubulovillous, 
± snaking, 
branching 
 Tubulovillous and 
cribriform 
 Index of structural 
atypia 
 Normal 
 Increased 
2 Histopathology of Early Mucosal Neoplasias
22
 The macroscopic type (Paris classifi cation, Fig. 4.2 ) is another indicator of risk 
of lymphatic and/or vascular spread of early cancer [ 1 – 4 , 15 ], probably refl ecting 
heterogenous morphogenic and molecular pathways of oncogenesis (compare 
Sect. 2.2 on pathways of colonic carcinogenesis). 
 Poorly or undifferentiated early cancers (G3/G4) show loss of cell–cell adhe-
sion, discontinuous growth pattern, high nucleus/cytoplasm ratio paralleled by more 
rapid tumour cell replication/proliferation, and higher metastatic potential (e.g. 
anoikis) on a cell biology level. Therefore, lymphatic vessel or blood vessel perme-
ation is frequent with even small, poorly differentiated intraepithelial early cancer, 
and so are higher rates of lymph node (or haematogenous) metastases as compared 
with well-differentiated mucosal cancer [ 2 , 15 , 17 ]. The risk of metastatic spread to 
locoregional lymph nodes is increased for poorly differentiated early gastric cancer 
exceeding lateral extension of 20 mm [ 2 , 17 ]. Also, margins of undifferentiated 
mucosal cancers tend to be less clear, the epithelial surface structure in the central 
part of the cancer may be destroyed by epithelial invasion with undifferentiated 
cancer cells, and the microcapillary pattern in the lamina propria mucosae tends to 
be very irregular on magnifying NBI endoscopy. 
 Based on extensive quantitative histopathologic analysis of surgical resection 
specimens of early gastrointestinal cancers, the likelihood of cure from early cancer 
achievable by endoscopic en bloc resection with free margins can now be predicted 
on based histologic characteristics, lateral size, depth of submucosal invasion, 
absence of lymphovascular invasion, and organ location in the GI tract (Table 2.4 
Criteria of curativeresection ). Magnifying endoscopic analysis of early cancers 
attempts to predict from characteristic alterations of the macroscopic type, surface 
and microvascular structure, whether the lesion allows endoscopic resection en bloc 
for cure ( Indication criteria , see Chaps. 3 and 6 – 10 ).
 Table 2.3 Probability of lymph node metastasis of superfi cial cancers by extent of submucosal 
invasion (μm) 
 Carcinoma Depth of invasion LN pos. cases (%) 
 Oesophagus [ 3 , 16 , 18 , 20 , 21 ] 
 SCC ( type 0–II; grading G1, G2 ) m1 0 % 
 if L0, V0, d <5 cm, no ulcer, cN0 m3 (muscularis mucosae) 8 % 
 sm1 (<200 μm and d <5 cm) 4.2 % 
 Overall sm1 (<200 μm) 17 % 
 AC (CLE Barrett’s) pT1m 1.9 % (CI 1.2–2.7 %) 
 pT1sm 21 % 
 Stomach ( if L0, V0 ) [ 2 , 17 ] 
 AC intestinal type G1–G2 pT1m (d <30 mm) 0 % (CI 0–0.3 %) 
 pT1sm1 (<500 μm) 0 % (CI 0–2.5 %) 
 AC undifferentiated G3–G4 pT1m (d <20 mm, no ulcer) <1 % (CI 0–2.6 %) 
 Colon [ 1 , 19 ] (if G1 or G2, L0, V0 ) 
 AC type 0–II pT1 (sm <1,000 μm) 1.4 % (0–5 %) 
 AC type Ip pT1 (Ip-head, sm < 3,000 μm) 0 % 
D. Neureiter and T. Kiesslich
23
2.2 Characteristics of Colonic Neoplastic Lesions 
 On colonoscopy, most protruded or fl at lesions classify as adenomatous or hyper-
plastic according to histomorphology – see Fig. 2.1 . Whereas strictly hyperplastic 
lesions are non-neoplastic, the similarly looking serrated adenomas are – like pol-
ypoid adenomas – cancer precursor lesions.
 The usual perception of morphological carcinogenesis still focusses on the classi-
cal “polyp–cancer sequence” [ 23 ], although at least four other precursor–cancer path-
ways exist in the colon – the depressed neoplasia pathway, non-polyposis (HNPCC) 
pathway, serrated adenoma pathway, and in ulcerative colitis and in colitis Crohn the 
“infl ammation–dysplasia (DALM)–carcinoma pathway” [ 1 , 4 , 7 , 23 – 27 ] (Table 2.5 ).
2.2.1 Classical Polypoid Adenoma–Carcinoma Pathway 
 Polyps have been snared in the colon since 1972, and histologic observations led to 
the polypous adenoma–dysplasia–cancer sequence [ 29 ] that had been translated 
into molecular pathways of oncogenesis by Vogelstein et al. [ 23 ]. In addition, 
screening colonoscopy with clearing of all detectable adenomas by endoscopic 
polypectomy had reduced the incidence of CRC far below predicted rates [ 30 ]. 
This served as rationale for the approval of colonoscopy screening to prevent 
 Table 2.4 Criteria of curative endoscopic resection in oesophagus, stomach, and colorectum 
 Organ Criteria of curative resection en bloc 
 A. Stomach 1 . Guideline criteria 
 m-ca, diff. type, ly (−), v (−), Ul (−), and ≤2 cm in size 
 2 . Expanded criteria 
 m-ca, diff. type, ly (−), v (−), Ul (−), and any size >2 cm 
 m-ca, diff. type, ly (−), v (−), Ul (+), and ≤3 cm in size 
 sm 1-ca (invasion depth <500 μm), diff. type, ly (−), v (−) 
 m-ca, undifferentiated type (G3), ly (−), v (−), Ul (−), and size <2 cm 
 B. Oesophagus 
(squamous lesions 
only) 
 1 . Guideline criteria 
 1) pT1a-EP-ca, 2) pT1a-LPM-ca 
 2. Expanded criteria 
 pT1a-MM-ca, ly (−), v (−), diff. type, expansive growth, ly (−), v (−) 
 cT1b/sm-ca (invasion depth <200 μm), ly (−), v (−), infi ltrative 
growth pattern, expansive, diff. type, ly (−), v (−) 
 C. Colorectum 1. Guideline criteria 
 m-ca, diff. type, ly (−), v (−) 
 sm-ca (<1,000 μm), diff. type, ly (−), v (−) 
 Modifi ed from Toyonaga et al. [ 22 ] 
 m mucosal, ca cancer, diff differentiated, ly lymphatic invasion, v vascular invasion, Ul ulceration, 
 sm submucosal, EP epithelium, LPM lamina propria mucosae, MM muscularis mucosae 
2 Histopathology of Early Mucosal Neoplasias
24
CRC in the USA and many Western countries. From an endoscopic vantage point, 
Kudo et al. [ 4 ] and Uraoka et al. [ 31 ] described a separate entity – superfi cially 
spreading adenomas of more than 10 mm diameter – as lateral spreading type 
neoplasias (LST) which require an ablative strategy of its own. 
Adenoma
Protruded (Ip, Isp, Is)
Elevated (IIa)
Flat (IIb)
Depressed (IIc)
Tubular (t)
Tubulo-Villous (tv)
Villous (v)
Serrated
adenoma (sa)
Is or IIa
Hyperplastic
polyps (hp)
Is or IIa
Is
t
IIa
t
Is
sa
Is
hp
IIc
t
Is
tv
Is
sa
IIa
hp
100 µm 100 µm 50 µm 100 µm
100 µm 500 µm 50 µm 50 µm
 Fig. 2.1 Principles of histomorphology of adenomatous or hyperplastic mucosal lesions in the 
colon 
 Table 2.5 Morphogenic pathways of colorectal carcinogenesis 
 Superfi cial neoplasms CRC risk estimates Precursors of CRC (estimated) 
 1. Classical adenoma 
 Polypoid (type 0–Ip,s) 
 Distal > proximal 10 years 
 CIN (LoH, kRAS, APC) 15–30 % 60 % 
 2. Serrated adenoma 
 Serrated polyp (kRAS), distal 5 years 
 Sessile SA (BRAF), proximal 60 % ~10 % 
 CIN (kRAS) 
 MSI+++ (BRAF, CIMP) 
 3. Depressed NpI 0–IIc 1–< 5 years 25–30 % 
 “De novo cancer” 75 % 
 Proximal > distal 
 MSI+++ 
 4. HNPCC adenoma 
 Flat adenoma 0–IIa/b/c 1–5 years ~5 % 
 Proximal (70 %) > total colon 40–80 % 
 MSI+++ (MLH mut, CIMP) 
 According to refs. [ 1 , 4 , 6 , 7 , 26 , 28 ] 
 
D. Neureiter and T. Kiesslich
25
2.2.2 Flat/Depressed Colonic Adenoma–Carcinoma Pathway 
 The majority of advanced CRC may develop from a non-polypoid precursor lesion 
[ 1 , 4 , 32 , 33 ]. In the “depressed neoplasia–carcinoma sequence”, minute “de novo” 
cancers of 2–5 mm size, most with submucosal invasion, have been described by 
Shimoda et al. [ 33 ]. In more than 1,000 colonic neoplasms, they diagnosed 71 cancers, 
and 78 % of these originated from non-polypoid precursor lesions and 22 % from pol-
ypoid adenomas. Ten of 75 cancers were minute (<5 mm) depressed-type cancers with-
out adenomatous areas, but all of them with submucosal invasion. Depressed-type 
(0–IIc) colorectal carcinomas are at a more advanced stage than non-depressed lesions 
(0–IIa or b) [ 4 , 6 ]. Therefore, these depressed-type neoplasms have a high likelihood of 
malignant progression and tend to show shorter evolution time to cancer. 
2.2.3 Serrated Adenoma–Carcinoma Pathway 
 Sessile serrated adenomas show the endoscopic appearance and pit pattern (type II) of 
hyperplastic polyps, whereas polypoid (i.e. “traditional”) serrated adenomas mainly 
exhibit adenomatous pit pattern (pp IIIL or IV) [ 26 , 32 ]. However, these lesions are 
premalignant via the “serrated pathway” to adenocarcinoma [ 7 , 25 , 26 , 32 , 34 ]. About 
8 % of all and 18 % of proximal colorectal carcinomas originate from the “serrated 
pathway” involving the sequence hyperplastic aberrant crypt foci → hyperplastic 
polyps (HP) or sessile/polypoid serrated adenomas (SSA/TSA) → admixed polyps 
(serrated adenoma with dysplastic focus) → cancer [ 32 ]. Sessile serrated adenomas are 
located mainly in the proximal colon, traditional polypoid serrated adenomas more 
often (>60 %) in the left hemicolon [ 26 , 32 ]. Serrated adenomas show about twice as 
frequent malignant transition than classical polypoid adenomas. On a molecular basis, 
serrated polyps are the precursors of type 1-CRC (CIMP-high/MSI-high/BRAF muta-
tion) and type 2-CRC (CIMP-high/MSI-low/MSS/BRAF mutation) [ 7 , 35 ]. 
2.2.4 Hereditary Non-polyposis Colon Carcinogenesis 
 Hereditary non-polyposis colon cancer (HNPCC) shows a right-sided (~70 %) or 
even (30 % of cases) colonic distribution of cancer and mainly non-polypous pre-
cursor lesions (0–IIa and 0–IIb) with predominant villous architecture, containing 
high-grade dysplasia as well as mucinous differentiation [ 36 – 42 ]. On initial and 
follow-up surveillance colonoscopy, detection rate for non-polypoid adenomas is 
about 1.1 per patient[ 37 , 39 ]. The progression to HGD is more common in proximal 
than in distal HNPCC adenomas [ 42 ]. A high proportion of these non-polypoid 
adenomas will rapidly progress to cancer – CIMP-negative and with microsatellite 
instability (MSI-high) or chromosomal instability (and MS-stable) [ 7 , 43 ]. 
2 Histopathology of Early Mucosal Neoplasias
26
2.2.5 Dysplasia-Associated Lesion or Mass (DALM)–Cancer 
Pathway in Ulcerative Colitis 
 Patients with ulcerative colitis or colitis Crohn may exhibit three different types of 
neoplastic lesions: sporadic adenoma ( or adenoma - like DALM ), non - adenoma - like 
DALM , and fl at dysplasia [ 44 ]. 
 Sporadic adenomas are adenomas in the part of the colon not involved in ulcer-
ative colitis (or colitis Crohn) and without dysplasia of the surrounding fl at mucosa 
(which shows pit pattern I or II). Similar lesions are protruding “ adenoma-like 
DALMs ” in non-dysplastic mucosa with chronic ulcerative colitis [ 45 ]. Endoscopic 
ablation is indicated, but they carry a low risk (0–4.6 %) of associated dysplasia or 
cancer in the colon [ 46 ]. 
 DALM are raised dysplastic lesions with concomitant dysplasia of the surround-
ing fl at mucosa (showing pit pattern IIIL, IV, V) – also termed “ non-adenoma-like 
DALM ”. This appears to be a “fi eld cancerisation defect” on the basis of an infl am-
mation–dysplasia–cancer sequence [ 24 , 47 ] and has a high probability (38–84 %) of 
synchronous or metachronous cancer in chronic ulcerative colitis or colitis Crohn 
[ 24 , 47 ]. Therefore, (sub)total colectomy is recommended for “non-adenoma-like 
DALM” in ulcerative colitis [ 44 ]. 
 Flat dysplasias are similar to lesions type 0–IIb–c, sometimes even unrec-
ognisable in chronic inflamed mucosa. In the case of high-grade dysplasia 
(HGD), cancer may already be present in 42–67 % of patients [ 44 , 47 ]. 
Colectomy is recommended for fl at HGD to prevent synchronous and metachro-
nous cancer [ 44 ]. 
 A prospective study on fl at low-grade dysplasia (LGD) found only a 3 % initial 
rate and a 10 % rate of subsequent progression to CRC within 10 years [ 48 ]. 
However, a more recent meta-analysis (477 patients) indicated that fl at low-grade 
dysplasia (LGD) had a risk of 22 % for synchronous cancer and a 5-year progression 
rate of 33–53 % to advanced neoplasia (CRC or HGD) [ 49 ]. 
2.3 Characteristics of Gastric Carcinomas 
 Gastric adenocarcinomas occur in approximately 90 % of cases sporadically and 
in 10 % as inherited – the latter comprise at least three forms: familial diffuse 
gastric cancer ( FDGC ), familial intestinal gastric cancer ( FIGC ), and hereditary 
diffuse gastric cancer ( HDGC ) which is caused by CDH1 germline mutations 
encoding the cell-adhesion protein E-cadherin [ 50 ]. The two main histogenetic 
types of gastric cancer are the intestinal type forming gland-like tubular structures 
(most with grading G1 or G2) and the diffuse type lacking cell cohesion and infi l-
trating the gastric wall by spreading of single cancer cells (grading G3) (Fig. 2.2 ) 
[ 8 , 51 , 52 ].
D. Neureiter and T. Kiesslich
27
2.3.1 Intestinal-Type Gastric Adenocarcinoma 
 Intestinal-type cancer comprises two major histogenetic phenotypes – the intestinal 
phenotype and the gastric phenotype [ 9 , 53 ]. The classical intestinal phenotype 
arises in chronic atrophic gastritis (either autoimmune type A or Helicobacter 
pylori -induced type B gastritis) via the “immature” intestinal metaplasia to fl at or 
adenomatous intraepithelial neoplasia and fi nally the gland-forming intestinal-type 
carcinoma which frequently shows solid tumour growth and less invasion [ 9 , 53 , 54 ]. 
Intestinal metaplasia with HGIN has a 33–85 % chance to progress to gastric cancer 
[ 55 ]. Quite seldom are sporadic gastric adenomas that carry a 35 % chance of carci-
nomatous foci [ 55 ]. 
 Early gastric cancers of the intestinal type may exhibit any of the macroscopic 
lesions (0–Ip/s, 0–IIa/b/c, 0–III). Polypoid adenomas play a minor role as precursor 
a
b
50 µm
200 µm
 Fig. 2.2 Typical 
histomorphology of intestinal 
type ( a ) and diffuse/signet 
ring ( b ) gastric 
adenocarcinoma indicating 
the different growth pattern 
of well-defi ned glands in 
intestinal type in contrast to 
discohesive tumour sheet in 
diffuse type of gastric cancer 
 
2 Histopathology of Early Mucosal Neoplasias
28
lesion for gastric cancer, since <5 % of gastric cancers originate from 0–Is adenomas. 
The risk of submucosal invasion is high in types 0–Is and even higher in type 0–IIc 
[ 6 ]. The risk of lymph node metastasis is low (<5 %), when submucosal invasion is 
<500 μm (Ly 0, V 0), but is 21 % for invasion of sm2 >500 μm [ 2 , 17 ]. 
2.3.2 Gastric Phenotype Adenocarcinoma 
 The gastric phenotype carcinoma – frequently with microsatellite instability – devel-
ops from non-metaplastic gastric epithelium either “de novo” or from small adenoma 
of pyloric mucoid glands [ 54 , 56 ]. Gastric-type differentiated carcinoma represents 
8–24 % of early gastric cancers, often type IIb or IIc lesions with indistinct margins 
and less discoloured surface [ 53 ]. This type of cancer tends to be larger and more 
often exhibits submucosal invasion than the intestinal type [ 9 , 53 , 54 ]. Advanced 
gastric-type and intestinal-type cancers often express a mixed phenotype including a 
diffuse growth component caused by inactivation of the E-cadherin gene CDH1, 
e.g. by biallelic hypermethylation [ 54 ]. 
2.3.3 Diffuse/Signet Ring-Type GC (De Novo GC) 
 Early diffuse-type cancer shows either fl at (type 0–IIb) or depressed lesions (0–IIc), 
with diffusely infi ltrating single cancer cells in the mucosa and submucosa which 
exhibit massive cellular atypia (most with grading G3) [ 6 , 57 ]. Minute diffuse-type 
cancers (diameter <5 mm) are diffi cult to detect and most often appear as small or 
tiny pale spot in the gastric mucosa [ 57 ]. 
2.3.4 Hereditary Diffuse-Type Gastric Cancer (HDGC) 
 The origin of this cancer (caused by CDH1 germline mutations) in subjects 
<60 years old usually is multifocal synchronous, and neoplastic foci are very diffi -
cult to detect in affected individuals. Therefore, in suspected cases, the diagnosis 
must be established by molecular genetic analysis, starting with the index case in the 
kindred. Individuals with proven inherited genetic defect must undergo prophylactic 
gastrectomy [ 50 ]. 
2.4 Characteristics of Oesophageal Neoplastic Lesions 
 For both types of oesophageal cancer, squamous cell carcinoma as well as adeno-
carcinoma in columnar cell-lined (Barrett’s) oesophagus (CLE) (Fig. 2.3 ), chronic 
infl ammation of the oesophageal epithelium is the trigger of carcinogenesis. 
D. Neureiter and T. Kiesslich
29
The chronic oesophagitis–dysplasia–cancer sequence is maintained by a host of 
noxious agents in the former and mainly by gastro-oesophageal refl ux of acid and 
pepsin or bile in the latter [ 58 ].
2.4.1 Cylinder Epithelial Dysplasia–Cancer 
Pathway (Barrett’s Cancer) 
 Chronic erosive refl ux oesophagitis triggers mucosal healing by transition to more 
resistant columnar cell-lined metaplasia and fi nally dysplastic epithelium [ 59 ]. 
Additional risk factors are tobacco and alcohol abuse [ 58 ]. Nearly all adenocarcino-
mas of the distal oesophagus and the EG junction arise from Barrett’s epithelium via 
the sequence “intestinal metaplasia–dysplasia–carcinoma in situ”. In a high propor-
tion of early neoplasias, the Wnt-β-catenin pathway is activated and p53 mutated 
[ 60 ]. Low-grade dysplasia may either regress again or progress to high-grade 
intraepithelial neoplasia (HGIN) which carries on the average a 30 % chance of 
a
b
200 µm
100 µm
 Fig. 2.3 Histomorphology