Definition and Staging of Early Esophageal, Gastric and
Colorectal Cancer
Nikolas
Eleftheriadis, Haruhiro Inoue, Haruo Ikeda, Manabu Onimaru, Akira Yoshida,
Roberta Maselli,
Grace
Santi, Shin-ei Kudo
Nikolas Eleftheriadis, Haruhiro Inoue, Haruo Ikeda,
Manabu Onimaru, Akira Yoshida, Roberta Maselli, Grace Santi, Shin-ei Kudo, Digestive Disease
Center, Showa University Northern Yokohama Hospital, 35-1 Chigasakichuo,
Tsuzuki-ku, Yokohama 224-8503, Japan
Correspondence to: Nikolas Eleftheriadis, MD, Digestive Disease
Center, Showa University, Northern Yokohama Hospital, 35-1 Chigasakichuo,
Tsuzuki-ku, Yokohama, 224-8503 Japan.
Email: nikoseleftheriadis@yahoo.com
Telephone: +81-45-949-700
Received: May 8, 2014
Revised: June 10, 2014
Accepted: June 12, 2014
Published online: July 18, 2014
ABSTRACT
Accurate diagnosis
of gastrointestinal (GI) cancer in early stages, endoscopically showed as superficial
noninvasive lesions, is the current optimal strategy for optional outcome. Superficial
GI cancer is defined as both mucosal and submucosal cancer with or without
lymph node metastases. Curability however, is related to the risk of lymph node
metastases, which is the major factor related to long-term outcome. A concept
of early GI cancer therefore is local lesion which has no risk of lymph node
metastasis, while invasive cancer is a superficial cancer with
lymph node metastases. According to retrospective studies from surgically
rejected specimens of early stage GI cancer with extensive lymph dissection,
the rate of lymph node metastases was very low in mucosal carcinomas, which are
considered curable by endoscopic rejection alone, but much higher in cases of
submucosal invasion. For deep mucosal and slightly submucosal carcinomas there
are subtle but important organ specific differences with m3-sm1 esophageal
carcinomas to have high risk of lymph node metastases (>20%) despite the superficial
appearance, while for m3-sm1 gastric and colorectal lesions have low risk of
lymph node metastases and should be also considered for endoscopic treatment.
Accurately preoperative staging of GI cancer is the present difficulty in
clinics, which is vitally important for choosing appropriate treatment method.
Chromoendoscopy in combination with high-resolution, magnification endoscopy
and narrow band imaging (NBI) system has been introduced in clinical setting in
order to identify subtle GI lesions. The combination of all these techniques
permitted real time accurate endoscopic diagnosis of early GI cancer. Moreover,
in Japan they have already established standardized endoscopic classifications
for staging early GI cancer, using combined macroscopic classification,
chromoendoscopy and NBI magnification endoscopy Pit pattern classification is
described for colorectal lesions for years. Using NBI magnification it has been
established the IPCL pattern classification for early stage easophageal cancer,
while for gastric and colorectal cancers there have been described specific NBI
magnifying classifications. Based on these classifications a real-time,
reliable endoscopic diagnosis of early GI cancer can be made.
© 2014 ACT. All
rights reserved.
Key words: Early gastrointestinal cancer; Definition; Lymph node metastases;
Staging
Eleftheriadis N,
Inoue H, Ikeda H, Onimaru M, Yoshida A, Maselli R, Santi G, Kudo S. Definition and
Staging of Early Esophageal, Gastric and Colorectal Cancer. Journal of Tumor 2014; 2(7):
161-178 Available from: URL: http://www.ghrnet.org/index.php/JT/article/view/775
INTRODUCTION
According to Paris[1] classification of superficial
gastrointestinal (GI) lesions: in the esophagus, stomach and colon,
neoplastic lesions of the digestive tract are called superficial at
endoscopy, when the endoscopic appearance suggests either a small cancer or a
noninvasive neoplastic lesion (dysplasia/adenoma), while WHO[2]
defined superficial GI cancer as both mucosal and submucosal cancer
with or without metastases[3-5]. Superficial tumors
correspond to the T1 stage of the TNM[3-5] classification, in which
invasion is limited to the mucosa and submucosa (Tables 1, 2 and 3)[3-5].
Superficial tumors are non-obstructive, usually are asymptomatic and
often are detected as an incidental finding or by screening.
The term superficial,
however, is in some way confusing, because it is not directly related to
histology or invasiveness of a GI cancer, but simply describes the endoscopic
appearance of a lesion, which looks to be restricted to superficial
layers of GI tract.
Instead of the
term superficial, more accurate and clinically useful should be the
term early GI cancer, which suggests a curable disease and has been already
used and defined in Japan for decades[3-5].
Curability of
early stage GI cancer is related to the risk of lymph node metastases, which is
the major factor related to long-term outcome of the GI cancer[6,7].
A concept of early cancer therefore is local lesion which has no risk of lymph
node metastasis.
One of the
major factors that found to be related to the risk of lymph node metastases is
the depth of invasion (mucosal versus submucosal)[8]. Infiltration
pattern B, C and vessel permeation (ly, v) are another independent risk factors
for lymph node involvement.
Depth of
invasion and risk of lymph node metastases
According to review studies from surgically rejected specimens of early
stage GI cancer with extensive lymph dissection, the rate of lymph node
metastases was very low in mucosal carcinomas, 2%-4% for gastric[8-11],
2% -3% for esophageal[12,13], and 0% for colorectal carcinomas[14-16],
but much higher in cases of submucosal invasion; namely 14-20% for gastric[10,17],
37-53% for esophageal[12] and 3% -18% for colorectal carcinomas[14-16]
(Tables 4, 5).
Further
subclassification of mucosal (m1-3) and submucosal (sm1-3) GI cancers,
according to the depth of invasion (Figure 1), has been proposed in Japan, in
order to select those patients with minimal risk of lymph node metastases, who
would benefited from endoscopic treatment[2-4,18].
This
subclassification was possible, after review studies of mucosal and submucosal
thickness in surgically rejected specimens from early stage esophageal, gastric
and colonic cancer and subsequent division of the submucosal space into three
equal parts[3,5,6,18].
This precise
subdivision into six layers has been proposed because the risk of nodal
metastases increases from nil to high with the depth of invasion in the
successive layers of the mucosa and submucosa and because they have already
established endoscopic classification system for predicting the depth of
invasion using combined macroscopic classification, chromoendoscopy and NBI
magnification endoscopy and lately endocytoscopy[19-25]. The
combination of all these techniques permitted the real time accurate endoscopic
prediction of the depth of invasion for otherwise superficial lesions.
This is important for precise definite treatment decision (endoscopic versus
surgery). In Japan it has been already established treatment guidelines based
on these classifications for GI superficial cancers[26,27].
The correspondence between depth of invasion and the most appropriate treatment
is shown in table 6.
Submucosal 1
(Sm1) GI carcinoma, was then defined, as carcinoma invading the upper one third
of the submucosa and was estimated for esophageal cancer less than 200 m, (sm1
esophageal cancer)[6,18], for sm1 gastric cancer less than 300 m
and less than 500 m for sm1 colon cancer, respectively[26,28,29].
According to
these sub classifications, in all types of GI cancer-esophageal, gastric and
colorectal cancer- m1 and m2 GI carcinomas have no risk of lymph node
metastasis and are considered curable by endoscopic rejection alone, while
sm2-sm3 have high risk of lymph node metastasis (up to 49%)[3-6,32]
and should be treated by surgery. (Table 5, Figures 2 A-C)[10,12,16,17].
Regarding m3 and sm1 subtypes and risk of lymph node metastases, there are
subtle but important differences between the different GI organs, which are
presented below. It is obvious therefore that the term superficial
used in Paris classification[1] is not equal to the term early GI
cancer used here, while detailed histological classification (mucosal versus
submucosal) of early stage GI cancer is of great importance.
Esophageal
cancer: Depth of Tumor Invasion (T)
Particularly, for esophageal squamous cell (SCC) carcinoma (figure 2A),
up to 10% of m3 carcinomas and about 20% of sm1 esophageal SCC have lymph node
metastasis and are not absolutely indicated for endoscopic treatment[5,35]
(Table 7).
In conclusion,
in esophageal SCC, m1 and m2 lesions have no risk of lymph node metastases and
are absolutely indicated for endoscopic treatment, while sm2-sm3 and the
majority of m3 and sm1 have high risk of lymph node metastases and should be
treated by surgery.
Lately, some
subtypes of m3-sm1 esophageal SCCs, which present specific narrow band imaging
(NBI) pattern (IPCL-V3A pattern classification, Inoues classification[36])
(Figure 14), had no risk of lymph node metastases despite the superficial
submucosal invasion and are also relative candidates for endoscopic rejection
(endoscopic submucosal dissection). According to this data, early esophageal
carcinoma is defined the superficial mucosal carcinoma with m1-m2
invasion and m3-sm1 subtype with IPCL-V3A NBI pattern classification[36].
The type T1 of
esophageal cancer [tumor confined to mucosa (M) or submucosa (SM), according to
TNM classification2], was further divided into two groups: T1a
(mucosal cancer) and T1b (submucosal cancer) (Table 1). The T1a was further
subdivided into three groups: T1a-EP (carcinoma in situ, Tis), T1a-LPM (tumor
invasion through the lamina propria mucosa) and T1a-MM (tumor invasion to the
muscularis mucusae). The depth of invasion in the submucosa (T1b) is divided
into 3 sections of equivalent thickness: superficial (SM1), middle (SM2)
and deep (SM3) (Table 1).
The relation
between macroscopic classification of type 0 esophageal SCC and depth of
invasion is shown in table 8[27]. According to this multicenter
analysis conducted in Japan, protruding type 0-Ip+Is and excavated type
0-III esophageal lesions had higher risk of deep submucosal invasion (79% and
84% respectively)[27].
Gastric cancer:
Depth of Tumor Invasion (T)
In stomach, no risk of lymph node metastases was found for gastric m3,
sm1 cancers, while sm2-sm3 lesions have high risk of lymph node metastases
(>20%)[8-11,17]. (Table 5, figure 2B)[37].
Especially for
gastric cancer, a simplest two-grade classification (sm1 and sm2) in regard to
the invasion depth has been proposed. Sm1 gastric cancer is defined as
submucosal penetration less than 500m from muscularis mucosa and Sm2 as
invasion of 500 m or more (Figure 3).
Gotoda et
al[29] in a large number of patients with early stage gastric
cancer found that sm1 (<500 m) gastric lesions had lower risk of lymph node
metastases and when they were combined with other independent risk factors such
as (a) differentiated type; (b) size smaller than 30 mm and (c) absence of
lymphatic-vascular involvement, no lymph node metastases were found in patients
with sm1 (<500 m) submucosal gastric cancer[29].
The two grade
classification of the submucosal gastric cancer (sm1, sm2) is more practical
and useful and it was adapted in TNM classification (JCGC[38])
(Table 9). The type T1 of gastric cancer (tumor confined to mucosa (M) or
submucosa (SM), according to TNM classification[2]), was further
subclassified into T1a (mucosal cancer) and T1b (submucosal cancer) and the T1b
was further subclassified to SM1 or T1b1 (tumor invasion within 0.5 mm of muscularis
mucusae) and SM2 or T2b2 (tumor invasion is 0.5 mm or more deep into the
muscularis mucosae) (Table 2 and 9).
This
subclassification was imposed from the necessity to accurate distinguish
endoscopically curable early gastric cancer. This subclassification was
absolutely necessary in the era of endoscopic submucosal dissection (ESD) en
block rejection of early GI cancer.
Further
clinical studies by Gotoda[31] and colleagues from large number of
surgically treated patients with early stage gastric cancer, were able to
identify additional groups of patients with no or lower risk of lymph node
metastases than the risks of mortality from surgery[31].
Except for the
submucosal invasion depth, other risk factors such as tumor size, histological
type and lymphatic-vascular involvement, were also found to be independently
related to the risk of lymph node metastases in submucosal gastric cancer[29].
Histologically well and moderately
differentiated tubular adenocarcinoma and papillary adenocarcinoma were
classified as differentiated histological type; poorly differentiated
adenocarcinoma and signet-ring cell carcinoma were classified as undifferentiated
histological type[39,29]. Regarding early gastric cancer tubular and
papillary variants represent 50% and 30% respectively of cases. Signet ring
cell carcinoma and poorly differentiated carcinoma represent 25% and 15%
respectively and are usually depressed or ulcerated[2].
Initial
studies demonstrated, that undifferentiated mucosal gastric adenocarcinomas,
even in absence of submucosal invasion, had higher probability of lymph node
metastases (4.2%) compared with differentiated mucosal gastric carcinomas
(0.4%) and are not absolutely considered for endoscopic treatment (EMR/ESD)[31,40,41].
Subsequent
studies, however, showed that other factors as well, such as tumor size,
lymphatic invasion, depth of invasion and ulceration had predictive value on
the risk of lymph node metastasis in undifferentiated gastric adenocarcinomas.
Particularly, gastric tumor less than 20 mm in size, confined to the mucosa,
without lymphatic invasion or ulceration had very low risk for lymph node
metastases and could be considered for curative ESD resection[31,42,43].
Under these conditions endoscopic treatment is currently recommended for
undifferentiated gastric adenocarcinomas (relative indication)[31,42-44]
(Table 6, figure 4 and 5D).
There are also
cases of early signet cell gastric carcinoma that have been complete rejected
by ESD, such as a case from the Showa University, Northern Yokohama Hospital,
Japan shown in figure 4.
Further
clinical studies by Gotoda[31] and colleagues from large number of
surgically treated patients with early stage gastric cancer, were able to
identify additional groups of patients with no or lower risk of lymph node
metastases than the risks of mortality from surgery[31].
These results
allowed the development of an expanded list of candidates with no risk of lymph
node metastases, suitable for endoscopic resection for early gastric cancer, as
shown in table 10. The rationale of this recommendations is based upon the
knowledge that larger-size lesions or lesions with undifferentiated histology
type are more likely to extend into the deep submucosal layer and thus have a
higher risk of lymph node metastases[29-31,45].
Moreover,
according to study by Tsujitanui et al[45] early stage
gastric cancer depressed type (0-IIc) of less than 1 cm in diameter and the
elevated type (0-IIa) of less than 2 cm in diameter are suitable for endoscopic
treatment (EMR/ESD) (Table 11 and figure 5).
According to
the results of this study, in superficial gastric cancer, elevated type
of more than 3 cm (0-I) and depressed type of 1 to 3 cm in diameter (0-III)
were related to high risk of lymph node metastases and should be treated
surgically, while depressed type of less than 1cm in diameter (0-IIc) and the
elevated type (0-IIa) of less than 2 cm in diameter are suitable for endoscopic
treatment (EMR/ESD) (Tables 10 and 11).
The presence
of lymph node metastasis is the most important prognostic factor for superficial
gastric cancer. Because radical surgery with lymph node dissection has provided
an excellent therapeutic outcome in early stage gastric cancer, with 5-year
survival rate after curative resection more than 90% including recent European
studies[29], precise diagnosis (pick up) of early gastric cancer and
accurate indications for local EMR/ESD rejection, are fundamental for optional
curative outcome.
As a result of
this policy, in cases with superficial gastric cancer with one or more
risk factors for lymph node metastases (Table 12), such as undifferentiated
type, size larger than 2 cm, the presence of lymphatic/venous involvement,
submucosal invasion and ulcerative change, gastrectomy with lymph node
dissection is recommended and usually performed, although the gastric lesion
can be complete removed by endoscopy[31,46].
However, in
similar cases with contraindications for major surgery due to comorbidities or
advanced age combined ESD rejection for the gastric tumor with laparoscopic
lymph node rejection has been reported to be efficacious, in small group of
patients with early stage gastric cancer, with one or more factors for lymph
node metastases[46]. Furthermore, ESD rejection does not preclude
future surgery, if needed. In contrast precise assessment of the en block
rejected specimen provide a complete biopsy, crucial for further treatment
planning (Figures 6 and 7). In view of these evolutions, a strict schedule was
adapted and proposed, according to the JCGC[38], for handling the
endoscopical rejected ESD specimen.
Colorectal
cancer: Depth of Tumor Invasion (T)
According to Japanese Classifications of Colorectal Cancers (JCCC)[5]
the depth of tumor invasion for colorectal cancer is as follow (Table 3):
M: Invasion
confined to mucosa
M: Invasion to
submucosal
MP: Invasion
to muscularis propria
For parts of intestine that have serosa/visceral peritoneum
SS: Invasion
to subserosa
SE: Invasion
penetrating serosa
SI: Direct
invasion to adjacent organs or structures
For parts of intestine that do not have serosa/visceral peritoneum
A: Invasion
through muscularis propria into pericolic or perirectal tissues
AI: Direct
invasion to adjacent organs or structures
In colorectal cancer
except for the depth of invasion important factor for lymph node metastases is
also the width of invasion (Figure 8).
Submucosal
colorectal cancers are divided into sm1, 2 and 3 according to depth of
invasion, while sm1 lesions are further divided into sm1a, 1b and 1c, according
to width of invasion as shown in figure 8[26]. When the width of the
submucosal invasion is less than the half of the total width, as in sm1a sm1b
lesions, there is no risk of lymph node metastases and they defined as slightly
invasive submucosal cancers (SMs). Sm1c (submucosal invasion more than the half
of the total width), sm2 and sm3 lesions show substantial proportion of lymph
node metastases (approximately 10%) and are defined massively invasive
submucosal cancers (SMm)[26]. According to this data early
colorectal cancer is defined the m1-m3 mucosal and sm1a, sm1b submucosal carcinoma,
while sm1c, sm2-sm3 are invasive cancer.
In conclusion
for colorectal cancer m3, sm1a and sm1b lesions had no risk of lymph node
metastases and are indicated for endoscopic treatment only, while sm1c, sm2 and
sm3 colorectal cancer has more than 10% risk of lymph node metastases and
should be treated by surgery[26] (Tables 4, 5 and figure 2C).
The relation
between macroscopic classification and size of type 0 colorectal cancer and
depth of invasion is shown in table 13. According to this Japanese data
presented in Paris classification[1], protruded type 0-Ip+Is, superficial
elevated and flat type 0-IIa+IIb colorectal lesions less than 15 mm have low
risk of submucosal invasion (<8%), while size more than >20 mm the risk
of submucosal invasion increased to more than 17%. Depressed type 0-IIc
lesions are related with the higher risk of submucosal invasion even in small
size (<5 mm)[47-49]. Type 0-IIc colorectal lesions with
diameter of more than 5 mm have >40% risk of submucosal invasion[48].
Based on the results of these studies specific treatment guidelines have been
recommended.
Definition
of Superficial, Mucosal, Submucosal, Early GI cancer
According to the results of the above-mentioned studies, Superficial,
Mucosal, Submucosal, Early GI cancer were defined as follow:
Superficial
GI cancer is defined both mucosal and submucosal cancer with or without
metastases[3-5] and generally corresponds to T1sm of TNM
classification[3-5] (Figures 2 A, B and C).
Mucosal cancer is
defined as cancer confined to mucosal layer and corresponds to intramucosal
cancer, T1m, T1a. (Figure 2 A, B, C, tables 1, 2, 3).
Submucosal cancer is
defined as invasive cancer to submucosal layer and corresponds to T1sm, T1b
(TNM classification[37], WHO[49]). (Figures 2 A, B, C and
tables 1, 2, 3).
As a
consequence of the above-mentioned results, taking into account the organ
specific differences of lymph node metastases organ specific definitions of
early GI cancer are proposed:
Early gastric cancer is defined as
mucosal (m1-m3) or upper submucosal (sm1 <500 m) carcinoma without lymph
node metastases and is corresponding to T1a and T1b1 of the TNM classification
(Figure 6 A-C).
Early esophageal cancer is defined as
upper mucosal (m1, m2) carcinoma without lymph node metastases and is
corresponding to T1a of the TNM classification.
Early colorectal cancer is defined as
mucosal (m1-m3) or slightly invasive submucosal (SMs=sm1a sm1b) carcinoma
without lymph node metastases and is corresponding to T1a and T1b1 of the TNM
classification.
All these
early GI cancers can curably be treated by endoscopic means (EMR or ESD).
In contrast to
early GI cancer, we would like to distinguish invasive superficial GI
cancer from advanced GI cancer.
Advanced GI cancer is a GI
cancer invading the muscularis propria or deeper (corresponding to T2-T4 of
Borrmanns macroscopic classification), in contrast:
Invasive cancer is a superficial
cancer with lymph node metastases, and organ specific definitions is as follow:
Invasive gastric cancer is defined as
deep submucosal (sm2 >500 m) carcinoma with lymph node metastases and is
corresponding to T1b2 of the TNM classification (Figure 7 a-d).
Invasive esophageal cancer is defined as
deep mucosal (m3) carcinoma and submucosal cancer (Sm2-Sm3), with lymph node
metastases, (no correspondence to TNM classification)
Invasive colorectal cancer is defined as
deep invasive submucosal (SMm=sm1c) carcinoma with lymph node metastases,
(correspond to T1b2 of TNM classification)
General
principles of preoperative staging of superficial GI neoplasms
Accurate preoperative staging of superficial GI neoplasms is the
present difficulty in clinics, which is vitally important for choosing
appropriate treatment method (endoscopic versus surgery). In the West,
endoscopists tend to base treatment decisions largely on tumor size and
location and on the histology of biopsy specimens. However, in Japan,
endoscopists have found that endoscopic classification of a GI lesion can be an
important determinant of treatment decision especially, when endoscopic therapy
should be applied. The high burden of GI cancer in Japan, forced Japanese
investigators to develop advanced imaging techniques for endoscopic detection
of very early GI cancer.
Based on the
knowledge of Japanese Society of Endoscopy, especially (JCGC, JSED, JSCCR)[3-5]
an international group of endoscopists, surgeons and pathologists proposed the
Paris endoscopic classification of superficial lesions of the esophagus,
stomach, and colon (Paris 2002)[1].
During the
past two decades however, Japanese endoscopists had learnt unlike the western
endoscopists, how to diagnose and endoscopically treat early stages GI
neoplasia. This goal was achieved by the earlier use of technical progress,
including high resolution magnifying endoscopes and enhanced imaging
capabilities, such as narrow-band imaging (NBI) system and mainly by precise
classification and treatment guidelines, including development guidelines for
minimal invasive endoscopic treatments[53].
Chromoendoscopy in combination with high-resolution, magnification
endoscopy and enhanced imaging technology such as NBI system has been introduced
in clinical setting in order to identify subtle lesions. These endoscopic
advancements were initially studied at leading Japanese medical centers and
resulted in precise endoscopic description, with accurate prediction of
invasion depth and optional treatment decisions.
In view of
these evolutions, revision of Paris classification is urgent, in order to
incorporate classifications based on the new imaging technologies.
Endoscopic
detection and chromoendoscopy
Recent models of videoendoscopes meet the requirements for the
acquisition of a high-quality digital image in terms of resolution, color
reproduction, contrast, and structure enhancement. The primary step in
diagnosis is to identify the presence of a mucosal area slightly discolored (more
pale or more red), an irregular microvascular network, or a slight elevation or
depression.
The second
step in diagnosis is based on chromoendoscopy, to help in the meticulous
description of the lesion. Chromoendoscopy should be readily available and should
be performed when a target lesion has been detected. The routine use of
endoscopic dyes to improve the imaging of a focal lesion does not mean that a
systematic application covering the entire mucosal surface must be performed in
every case. Diffuse staining to increase the yield of detection has, however,
been proposed in those at high risk of neoplasia (e.g., familial colorectal
cancer or ulcerative colitis).
A variety of
agents have been proposed for chromoendoscopy. Iodine solution (1.5%-2%), a
vital stain, is the basic agent used for the stratified squamous epithelium of
the esophagus[54,55]. Neoplastic areas remain unstained (negative
stain), in contrast to the dark brown positive stain of the normal epithelium.
The dye most
commonly used on abnormal areas of the stomach and the colon is indigo carmine
solution (0.5%-1%), a contrast stain. Chromoendoscopy with indigo carmine helps
in the distinction between non-neoplastic (hyperplastic) or neoplastic lesions
in the large bowel. Indigo carmine dye spraying, which is practiced routinely
in Japan[56,57], has been also used in the West[58-62]
but is still uncommon[63].
Methylene blue
chromoendoscopy has been used for the detection of intestinal metaplasia in the
esophagus and the stomach and has been used in the large bowel by spraying a
0.1% solution in successive segments[64-69]. In a recent randomized
study, this procedure was applied to the surveillance of patients with
ulcerative colitis[70].
An increased yield
of non-polypoid neoplastic lesions was obtained in the group of patients
evaluated with chromoendoscopy with magnification endoscopy[70].
Magnification optics were believed to be a major factor of improved efficacy[71].
The endoscopic application of dilute acetic acid has been proposed as a useful
agent in studying the architecture of the metaplastic mucosa in Barretts
esophagus[72,73] and lately in evaluation of early gastric cancer in
combination with NBI magnifying endoscopy[74].
Organ specific endoscopic
classifications of early GI cancer
NBI magnifying
esophagoscopy and IPCL pattern classification of early esophageal cancer
Magnification endoscopy combined with NBI constitutes a novel advanced
imaging technology, which enhances microvascular architecture of the superficial
esophageal mucosa and permits real-time, accurate diagnosis of superficial
malignant and premalignant esophageal lesions[75].
Stratified
squamous esophageal epithelium has no pit pattern, which is routinely observed
in glandular epithelium of stomach and colon, instead a specific superficial
capillary pattern, the Intra-epithelial Papillary Capillary Loop (IPCL), is
identified[36,76,77] (Figure 9). The IPCL, which rises
perpendicularly from the branching vessel, is barely recognizable under
conventional endoscopy. By using the magnifying scope, which has magnification
capability up to 80 times, the IPCL of the normal mucosa is identified as red
dots.
NBI enables
more vivid observation of the IPCL. Branching vessels which are located at the
relatively deeper layer are observed as green, and IPCL which is located at
more superficial layer, is observed as brown loops (brown dots)[76,78,79].
In esophagus due to relatively narrow lumen, there is sufficient light to
perform a complete visual survey of the mucosa under NBI imaging system.
In Japan, as
NBI imaging highlights better superficial malignant and premalignant
esophageal lesions than white light endoscopy, it is routine to begin the
diagnostic examination in esophagus with NBI with low optical magnification[77].
In the esophagus and pharynx, due to relatively narrow lumen, there is
sufficient light to perform a complete visual survey of the mucosa under NBI.
Any suspicious area is initially visualized as brownish area under NBI with
low magnification and is further evaluated with NBI high magnification in
combination with iodine (Lugol) chromoendoscopy.
All suspicious
brownish areas in esophagus are assessed with NBI high magnification
endoscopy (¡Á80), in order to
detect characteristic changes of IPCL pattern, which are directly related to
tissue atypism and cancer invasion depth[36,76,77]. Switch from NBI
to white light technique is easy accomplished just by pushing a button on the
top of the handle of the endoscope.
In superficial
squamous cell esophageal carcinoma (SCC), four main characteristic changes of
IPCL pattern have been detailed described (Figure 9)[80]: (a)
Dilation; (b) Tortuosity; (c) Caliber change in a single IPCL and (d) Variation
in the shape (uneven form) in multiple IPCLs.
Based on these
changes, IPCL pattern classification[36,75] systems of NBI
magnifying findings have been described in order to demonstrate the tissue
characterization for flat lesions (cancer versus non-cancer) and to predict the
depth of invasion[36,81-83,75,77,84] (Figure 10). According to IPCL
pattern classification, accurate selection of patients with early esophageal
cancer for endoscopic (EMR/ESD) versus surgical treatment can be accomplished[36,76,77,80].
The IPCL
pattern classification includes two sets of diagnostic criteria. IPCL pattern
classification from IPCL type I to Type V-1 (Figure 10) demonstrates the tissue
characterization for flat lesion (normal to mucosal cancer), while IPCL pattern
classification from type V-1 to type VN reflects cancer infiltration depth (m1,
m2, m3 Sm1 to Sm2) (Figures 10-14).
The IPCL
pattern is categorized from type I (normal mucosa) to type V (carcinoma)
(Figures 10,12 and 13):
IPCL Type I: corresponds to normal mucosa.
IPCL Type II:
is often equivalent to regenerative tissue or inflammation.
IPCL type III:
is a borderline lesion which potentially includes esophagitis, but is often
related to low-grade intraepithelial neoplasia (category 3 in revised Vienna
classification[85]) (table 14). IPCL type III should be considered
for further follow-up.
IPCL Type IV:
is equivalent to high-grade intraepithelial neoplasia or carcinoma in situ
(category 4.1 and 4.2 revised Vienna classification85).
IPCL Type V1: represent mucosal cancer (m1).
IPCL Type V2:
represent mucosal cancer (m2) (category 4.4 revised Vienna classification[85]).
Local
endoscopic treatment with EMR/ESD should be considered for IPCL type IV, type
V-1 and type V-2, which definitely represent Tis and mucosal cancer m1 or m2,
with no risk of lymph node metastases.
IPCL
Type V3 is subdivided into (Figure 14):
IPCL Type V3A: corresponds to non invasive mucosal cancer, m2 (category
4.4 revised Vienna classification[85]) which is considered for
endoscopic treatment (ESD).
IPCL Type V3B:
is referred to deep mucosal cancer m3 with submucosal invasion (Sm1) (category
5 revised Vienna classification[85]), which should be considered for
surgery as there is increase risk of lymph node metastases[36,76,77].
IPCL Type VN
corresponds to new tumor vessel, which is cancer often associated with deeper
invasion (sm2 or more) with significant risk of lymph node metastases and the
surgical treatment should be recommended[76].
The
above-mentioned IPCL pattern classification has been also used for detecting
and evaluating suspected superficial pharyngeal lesions and has been
found reliable and accurate method in guiding endoscopic rejection for
pharyngeal cancer as well[77,81,86]. In the oropharyngeal area
chromo-endoscopy is not possible and NBI imaging provides a virtual
chromoendoscopy with real time optical diagnosis.
NBI
magnification endoscopy in esophagus can be combined with chromo-endoscopy
using iodine (Lugol) stain upon indication, which remains the best sensitive
simple method for identification and precise delineation of squamous cell
intraepithelial neoplasia or early cancer in esophagus[87]. Lugol
chromoendoscopy in squamous cell epithelium reveals the pink color sign in
the non-iodine-stained lesions, which confirms the existence of carcinoma or high-grade
dysplasia. The pink color sign is recognized with NBI system as shiny silver
sign. Combination of both phenomena is called pink-silver sign[88]
(Figure 15). Shiny silver sing starts appearing around seven minutes after
iodine staining. This process will be shortened by spraying of sodium
thiosulfate solution, immediately after iodine staining[76].
However, NBI magnification imaging is superior to iodine crhomoendoscopy in
detecting the depth of invasion and defining the endoscopic respectability of superficial
early esophageal cancer.
NBI magnification imaging technique
has been extensively studied with promising results in evaluating esophageal
early SCCs, while the IPCL pattern classification has been proved reliable and
accurate method for exact diagnosis and treatment decision of esophageal superficial
SCCs[36,75-77]. NBI magnification imaging system has been proved
superior to conventional white light endoscopy in detection of early, even
minute <2 mm, esophageal SCC[76,78,79].
NBI magnifying endoscopic classification of early gastric cancer
NBI magnification endoscopy in stomach enhances both the microvascular
architecture and microsurface structure of the superficial gastric
mucosa, revealing specific NBI patterns and based on these findings a
real-time, reliable endoscopic diagnosis of early gastric cancer can be made,
according to several reports[82,89-91].
Although there
are no consistent guidelines for NBI magnification endoscopy for early gastric
cancer, there are specific NBI classifications for gastric lesions, described
in the literature[90,91]. Yao et al[90] first
reported the VS classification (V=vascular pattern, S=surface pattern) and
concluded that based on NBI magnification the major characteristic of early
gastric cancer is the presence of a demarcation line with either irregular
microvascular or irregular microsurface pattern[90].
Furthermore,
specific NBI magnifying findings of early gastric cancer are useful in
predicting the histological type. Particularly, differentiated type
adenocarcinomas are characterized by disappearance of regular subepithelial
capillary network (SECN), a demarcation line and irregular-microvascular
pattern (IMVP), while undifferentiated-type adenocarcinoma is characterized by
a reduced microvascular pattern[90].
Yokoyama et
al[91] recently described a four pattern standardized
classification- fine network (FNP), intralobular loop 1 (ILL1), intralobular
loop 2 (ILL-2) and corkscrew (CSP) system patterns - (Figure 16) of NBI magnifying
examination of early gastric cancer, which will be able to predict the
histological subtype of most gastric carcinomas.
According to
Yokoyama et al[91] differentiated-type adenocarcinomas mainly
showed FNP or ILL pattern, with more than 80% of differentiated type
adenocarcinomas were classified as ILL-1 or less ILL-2. Undifferentiated-type
adenocarcinomas were all classified as ILL-2 or CSP. These findings are of
great significance for treatment decision as differentiated early gastric
cancer is good candidate for endoscopic removal, while undifferentiated gastric
cancer may be invasive cancer.
Recently,
acetic acid spray further emphasized the superficial gastric mucosal
glandular structures and enhances the NBI magnifying endoscopic findings of
early gastric cancer, revealing specific abnormal endoscopic patterns, such as
small pit pattern, irregular villous pattern, or distorted pit pattern with
absence of glandular structures (Figure 17)[74].
Acetic acid
spray enhanced the accuracy of NBI magnification endoscopy in differentiating
malignant from benign superficial gastric lesions, especially in
controversial cases. A novel four-type NBI magnifying endoscopic classification
after acetic acid spray for early gastric cancer is also published[74].
Up to now NBI imaging in
combination with high resolution magnifying endoscopy is the acceptable
accurate method of choice for the preoperative evaluation of superficial
gastric lesions.
Pit pattern
and NBI magnifying endoscopic classification of early colorectal
cancer
Colorectal lesions are classified according to modified Japanese
classification of colorectal neoplasia[92] and Paris endoscopic
classification of early GI cancer[1] by configuration, as depressed
type (0-IIc), protruded type (0-Ip, 0-Isp, 0-Is) and flat type (0-IIa)[92,93]
(Figure 18).
Some elevated
colorectal lesions may reach a large (>10mm) lateral diameter without
increasing in their height or protrusion above the mucosa. These are called
Lateral Spreading Tumors (LST) and they tend to have a rather benign nature
despite their large size. Laterally spreading colorectal tumors were divided
into subgroups and are expressed as 0-IIa, 0-IIc+IIa, or 0-IIa+Is, according to
the categories of the Paris classification[1].
Magnification
colonoscopy enabled in vivo visualization of the fine surface
microstructure of various colorectal lesions, while the combination of
chromoendoscopy with magnifying colonoscopy is useful for detecting small
localized lesions, for differential diagnosis and for determining not only the
lateral extent but also the depth of a lesion.
Pit pattern
is the specific arrangement of the openings of the glands in various kinds of
colonic lesions under magnifying endoscopy[94,95]. Pit patterns
basically divided into normal, non-neoplastic (hyperplastic), and neoplastic
(adenomatous or cancerous) pattern. Although there are a variety of different
classifications the most frequently used is the one described by S. Kudo and
colleagues at the Akita Red Cross Hospital, which divides the pit patterns into
six groups: types I, II, IIIL, IIIs, IV, and V (Figure 19 and 20). Pit patterns
are useful in predicting the histological structure of a lesion. Particularly:
(1) The pits
of the normal mucosa (type I) are round and regular in size and arrangement.
(2) The pits of
non-neoplastic, hyperplastic polyps (type II) are larger than the normal pits,
and star-shaped or onion like, but are regularly arranged.
(3) In
polypoid adenomas, the pits often look elongated (type IIIL) The L stands for
Long or Large) and sometimes branched (type IV).
(4) Lesions
with compactly arranged pits smaller than the normal ones (type IIIS; the S
stands for small or short) are characterized depressed and tend to be early
cancers[96,97]. Such lesions are not frequent, but are highlighted
nowadays as candidate precursors of advanced cancers of de novo origin. The
small pits reflect straight and compactly arranged glands of the lesion. Type
IIIL and IIIS pits can be collectively called tubular pits.
(5) In
intramucosal cancer (which might be regarded as high-grade dysplasia in Western
countries) the pit pattern is fairly irregular (type V). In invasive cancer
reaching the submucosa and in advanced cancer the surface of the lesion is
rough and often ulcerated; therefore it is almost devoid of pits. This
non-structural pattern devoid of pits is also included in type V.
The
correspondence between type of pit pattern and histological findings is quite
well. Particularly, type II pit pattern is corresponding to non-neoplastic
lesions in more than 70%, type IIIL, IIIS and IV are corresponding to adenomas
in 79.6%, 86% and 75% respectively, type VI is corresponding to
carcinoma or high-grade dysplasia in 86% (61% carcinoma and 24% high-grade
dysplasia), and VN is corresponding to carcinoma in 93% (65% is corresponding
to submucosal invasive cancer).
The magnifying
colonoscope has opened the door to the new field of diagnosing colorectal
lesions. It is well established that histopathologic assessment of small
lesions by observation with standard endoscopic instruments is imprecise. By
magnifying endoscopy, however, it is possible to accurately differentiate true
neoplastic tumors from non-tumorous lesions. The routine usage of magnification
colonoscopy is assumed to reduce the requirement for biopsies and/or endoscopic
resections for the small and numerous surface abnormalities without overt
malignant pattern.
Furthermore,
NBI imaging system in colon as in other parts of GI tract reveals specific
vascular and mucosal patterns of superficial colonic lesions, which were
found effective in distinguishing neoplastic from non-neoplastic lesions, as
well as cancers from adenomas, with high accuracy (96.1%) in real time. NBI
imaging combined with magnifying endoscopy allows an estimate of the likely
histology of a polyp in vivo[26,98]. Wada et al[99],
described a standardized NBI magnifying endoscopic classification for
colorectal lesions and categorized vascular patterns of colonic neoplastic
lesions into six groups (Figure 21).
Particularly,
the normal colonic mucosa had a honey-comb-like vasculature (Figure 21A),
hyperplastic polyp has a faint pattern (Figure 21B) and tubular adenomas
showed a regular vessel-network pattern (Figure 21C) on NBI magnification. In
villous and tubulovillous adenomas, the vessels were well developed and rather
thick, which was the dense pattern (Figure 21D).
The NBI
magnifying vascular structure in high-grade colorectal adenomas and early
colorectal cancer varied depending on the different gross appearance of
lesions. Protruded high-grade adenomas showed either a vessel-network pattern
or a dense pattern (Figures 21 C and D). In protruded submucosally invasive
cancers, the vessels were thick and irregular. Definition for irregular vascular
pattern according to Wada et al[26] are (a) interruption of
the network; (b) a tortuous course of vessels and (c) unusually large caliber
of vessels (twice as large as that of surrounding vessels) (Figure 21E). In
contrast the depressed-type lesions, especially depressed invasive cancers were
characterized with decreased vessels, and this vascular pattern is called a
sparse pattern (Figure 21F).
Based on the
six patterns: normal, faint, network, dense, irregular and sparse of the
above-mentioned NBI magnifying classification, it is able to differentiate
neoplastic from non neoplastic colonic lesions with high sensitivity (83.5%),
specificity (98.7%) and accuracy (98.2%), according to Wada et al[9926,98].
Follow-up
after endoscopic treatment of early GI cancer
Accurate preoperative diagnosis and staging of early GI cancer, based
on the technique and classifications described in this article, followed by
precise patient selection for endoscopic (EMR or ESD) treatment according to
established guidelines, resulted in favorable long-term outcome after curative
endoscopic resections also for expanded indications in specialized centers[100-111].
Particularly,
according to recent meta-analysis the local recurrence after ESD for early
esophageal cancer was very low (0%-0.3% in mean observation period 19 months)
and significantly lower than EMR (9%-11% in mean observation period 30 months)[102,112-115].
Regarding, early
gastric cancer, the annual incidence (2.4%) of metachronous gastric cancer after
endoscopic (ESD) resection was constant, with low cumulative 3-year incidence
(3.3%-5.9%), while incidence of synchronous gastric cancer was also low (4%)[101,103,105-107].
Metachronous gastric cancers can be also treated curatively with repeat
endoscopic resection[116]. ESD for undifferentiated early gastric
cancer, is related to higher incidence of synchronous (14.5%) and metachronous
(8.5%) gastric cancer, although generally low[108,117].
In order to
detect synchronous or metachronous gastric cancer at an early stage, enough for
a curative repeat ESD, an annual endoscopic surveillance program is recommended[101].
Finally, local
endoscopic resection appears to be also effective for colorectal epithelial
neoplasms, (adenomatous polyps and early-stage carcinoma) with overall
favorable outcome[100,110,118,119.120]. Furthermore, en bloc
colorectal ESD resection resulted in better outcome than piecemeal EMR[100,110,118,119,121].
Colorectal ESD can be also successfully applied as first line salvage therapy
in treating residual or locally recurrent neoplastic disease with favorable
outcome alternatively to direct surgical resection[122].
Conclusions
The evolution in imaging technology (high resolution magnifying
endoscopes, combined with chromoendoscopy and enhanced imaging capabilities,
such as NBI technology) permitted the incorporation of endoscopic
classifications of GI lesions in clinical setting, making precise endoscopic
differential diagnosis (mucosal versus submucosal invasion) and staging of superficial
GI lesions possible. Subsequently reliable accurate real-time treatment
decisions (minimal invasive endoscopic versus surgical treatment) can be made.
In Japan there
are currently in use standardized endoscopic classifications for early GI
neoplasia. Pit pattern classification is used for colorectal lesions for years.
NBI magnification endoscopy in esophagus, stomach and colorectum enhances both
the mucosal microvascular architecture and microsurface structure, revealing
specific NBI patterns. The IPCL pattern classification for early esophageal
cancer and the NBI magnifying classifications for gastric and colorectal
lesions, currently used in Japanese centers, permitted in vivo
prediction of histology and are useful tools for reliable, real-time
preoperative staging of early GI cancer.
Local
treatment for mucosal GI cancer by endoscopic resection, either endoscopic
mucosal rejection (EMR) or endoscopic submucosal dissection (ESD) has been
generally accepted as an adequate therapeutic method in Japan, and is growing
in the West. In submucosal invasive cancer, however, surgery with complete
removal of lymph nodes has been recommended as the standard treatment, because
the high incidence of lymph node metastases (approximately 10-40%)[5,26,29,123].
Finally, in
stomach and colorectum, mucosal and slightly invasive submucosal cancer with no
lymph node metastasis are good targets for endoscopic local resection
(EMR/ESD), while in esophagus upper mucosal cancer only, without lymph node
metastases, is indication for endoscopic therapy (EMR/ESD).
CONFLICT OF
INTERESTS
There are no
conflicts of interest with regard to the present study.
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Peer reviewers: Chen Junqiang, Department of
Gastrointestinal Surgery, the First Affiliated Hospital of Guangxi Medical
University, No.6 Shuangyong Road, Nanning, 530021, P.R. China; Gian Luca
Baiocchi, Department of Clinical and Experimental Sciences, University of Brescia,
Spedali Civili, III Chirurgia, P.le Spedali Civili, 1, 25123 Brescia, Italy.
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