INDEX
Indications of Endoscopic Resection for Minimally Submucosa-Invasive Colorectal Carcinoma: Analysis of 330 Early Colorectal Carcinoma Lesions

Kenji TSUCHIDA1, Naotsuka OKAYAMA2, Yoshifumi YOKOYAMA2, Takashi JOH2,
Kyoji SENOO2, Mitsuki MIYATA2, Hirotaka OHARA2, Tomoyuki NOMURA2 and
Makoto ITOH2

1. Department of Internal Medicine, Nagoya City Johsai Hospital, 4-1 Kitabata-cho, Nakamura-ku, Nagoya 453-0815, Japan
2. First Department of Internal Medicine, Nagoya City University Medical School 1-Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan
Running title: Endoscopic resection of submucosal colon cancer
Key words: histologic type, shape, size, logistic regression analysis, impression of tenseness

Summary
Background and aim: Intramucosal and minimally submucosa-invasive colorectal carcinoma can be treated with endoscopic resection. This study was undertaken to develop the criteria which can be used to distinguish between these carcinoma and massively submucosa-invasive one as an aid in the development of a treatment plan.
Patients and methods: The sizes, shapes, histologic types, levels of invasion, and endoscopic findings of 330 early colorectal carcinoma resected endoscopically or by laparotomy were analyzed using a logistic regression analysis. Correlations between the histologic types, macroscopic findings (size and shape) or endoscopic findings, and the invasion levels of these lesions were investigated.
Results: Few (4%, 12/305) of the well-differentiated, but not other histologic type lesions contained massively submucosa-invasive carcinoma. Further, no superficially elevated, 4.3% (1/23) of the creeping (120 mm in size), and 2.2% (2/93) of the pedunculated tumors (8 and 30 mm in size) were also massively submucosa-invasive. Interestingly, a logistic regression analysis revealed that only the endoscopic finding, impression of tenseness, suggests massive invasion to the submucosa layer. The same analysis technique also indicated that all depressed and semipedunculated/sessile tumors over 20 mm in size could be massively submucosa-invasive.
Conclusions: Our data suggest that the early colorectal well-differentiated carcinoma which belongs to the superficially elevated type in any size, and the creeping or pedunculated type less than 20 mm in size can be treated with endoscopic resection. However, other histologic type and the depressed lesions as well as the semipedunculated/sessile ones over 20 mm in size should be resected by laparotomy. The lesions endoscopically presenting impression of tenseness should be also treated with laparotomy.

Introduction
Intramucosal colorectal carcinoma can be completely excised using an endoscopic resection technique because of the absence of metastasis to lymph nodes or vessels (1-4). Conversely, massively submucosa-invasive carcinoma should be treated with laparotomy. However, since recent progression in the endoscopic resection techniques has expanded the indications for target tumors, necessity of the additional laparotomy after the resection especially for the massively invasive lesions has increased (5). Recently, Tanaka et al. (6), Oohara et al. (7) , Ohta et al. (8), and Tanaka et al. (9) have reported that no metastasis to lymph nodes or vessels was found in minimally submucosa-invasive colorectal carcinoma when it was well-differentiated adenocarcinoma, so that the lesions of this type seem to be also the targets for endoscopic resection. For this reason, it would be useful to endoscopically distinguish between minimally and massively submucosa-invasive colorectal carcinoma before resection in order to reduce the unwarranted endoscopic resection for the later lesions.
In this study, the sizes, the shapes, the histologic types, and the endoscopic findings of colorectal carcinoma resected endoscopically or by laparotomy were analyzed partially using a logistic regression analysis, and their correlations to the levels of invasion were investigated in order to decide the indications of endoscopic resection for submucosa-invasive lesions.

Patients and Methods
Patients
For recent 7 years, 249 patients with 330 early colorectal carcinoma (one tumor: 201 patients, 2 tumors: 31 patients, 3 tumors: 7 patients, 4 tumors: 7 patients, 5 tumors: 2 patients, 8 tumors: one patient ) underwent endoscopic resection or laparotomy in the First Department of Internal Medicine, Nagoya City University Medical School (Nagoya, Japan), the Department of Internal Medicine, Koseiren Bisai Hospital (Aichi, Japan), and the Department of Gastroenterology, Gifu Prefecture Tajimi Hospital (Tajimi, Japan). There were 166 men with a mean age of 63.2 years (range: 39 to 84 years), and 83 women with a mean age of 65.1 years (range: 34 to 87 years). The 282 intramucosal colorectal carcinoma lesions were treated with endoscopic resection (n=245), or laparotomy (n=37), and the 48 submucosa-invasive carcinoma ones were also treated with endoscopic resection (n=20) or laparotomy (n=28).

Macroscopic, endoscopic, and histopathologic classification of colorectal carcinoma
The tumor size (mm) was measured along the major axis on the resected specimen. The macroscopic shape of the carcinoma was classified as elevated or depressed (10, 11). The elevated type was further subclassified as pedunculated (Ip), semipedunculated/sessile (Isp/Is), creeping (12), or superficially elevated (IIa) (10, 11). The lesions were also classified based on the histologic type and the level of invasion. The histologic types included well-differentiated, moderately-differentiated, poorly-differentiated, signet ring cell, and mucinous adenocarcinoma. The tumors were also classified according to the invasion level. The Japanese Classification of Colorectal Carcinoma proposed by the Japanese Society for Cancer of the Colon and Rectum (10) was used to distinguish between minimally and massively submucosa-invasive colorectal carcinoma. Carcinoma invading the submucosal layer to a depth less than 300m was considered minimally invasive.
Lymph node metastasis was diagnosed histologically in the laparotomy cases, and was diagnosed using computer tomography in the cases treated with endoscopic resection. The lymph node size over 1 cm was decided to be metastasis.

Endoscopic resection technique
Standard snare electrocautery techniques were used to endoscopically resect the Ip lesions. A modified endoscopic mucosal resection technique (13) was used for the Isp/Is, creeping, IIa, and depressed lesions. Briefly, after the tumor was identified using a video fiber optic colonoscope (Olympus CF-200I/CF-230I or CF-20I,. Tokyo, Japan), saline was injected into the submucosal layer under the tumor. The superficial-half of the elevated mucosa, including the tumor, was then resected using the specially designed hexagonal
Snare (13). This snare could be firmly fixed near the tumor with the attached needle, and completely encircled the lesions. The superficial-half of the elevated mucosa was resected because of avoiding damage to the muscle layer. A biopsy was performed using a diathermy (hot biopsy) to resect the tumors less than 5 mm in size.

Statistical analysis
A logistic regression analysis with the stepwize forward selection method was performed using a computer software; Statistical Analysis System (SAS, SAS Institute Co. Ltd). A p -value less than .05 was considered significant.

Results
Correlation between the histologic type and the invasion level
Table 1 shows the correlation between the histologic type and the invasion level of the resected colorectal carcinoma tumors. The rate of well-differentiated adenocarcinoma in all the tumors was 92.4%, and 6.4, 0.3, 0.6, and 0.3 % for moderately-differentiated, poorly-differentiated, signet ring cell, and mucinous adenocarcinoma, respectively. According to the results in Table 1, intramucosal or minimally submucosa-invasive carcinoma was found in 96 % (293/305) of the well-differentiated adenocarcinoma lesions. Conversely, more than 50 % of the signet ring cell and moderately-differentiated adenocarcinoma lesions were massively submucosa-invasive. Further, all of the poorly-differentiated and mucinous adenocarcinoma lesions were also massively invasive. There was no evidence of metastasis to the lymph nodes or vessels in any of the intramucosal or minimally invasive submucosal lesions (n=302), however 14.3 % (4/28) of the massively submucosa-invasive lesions (2 moderately differentiated, 1 signet ring cell, and 1 mucinous adenocarcinoma) had associated lymph node metastasis.

Correlation between the macroscopic finding (size and shape) and the invasion level
No massively submucosa-invasive colorectal carcinoma was found in the IIa lesions, whereas 2.2 % (2/93) of the Ip and 4.3 % (1/23) of the creeping tumors were massively submucosa-invasive (Table 2). Two of the three massively invasive lesions (1 creeping and 1 Ip ) were greater than 21 mm in size, and the size of the other one (Ip) was 8 mm. Massively submucosa-invasive carcinoma was also identified in the Isp/Is (7.3 %) and depressed (38.9%) tumors. Interestingly, 4 of which were less than 10 mm in size. These data suggest that any size of early colorectal carcinoma belongs to the IIa type, and the Ip or creeping type lesions less than 20 mm in size can be endoscopically resected when they were well-differentiated adenocarcinoma. However indication of endoscopic resection for the Isp/Is and the depressed lesions seem to depend on the size. In addition, there were 4 cases of positive lymph node metastasis; the shape, size, and histological type were as follows; Is/34 mm (moderately-differentiated adenocarcinoma), Isp/21 mm (signet ring cell carcinoma), Isp/16 mm (mucinous adenocarcinoma), and depressed/25 mm (moderately-differentiated adenocarcinoma).

Correlation between the endoscopic finding and the invasion level
The 41 submucosa-invasive colorectal carcinoma lesions (16 minimally and 25 massively) which were clearly observed by a colonoscope were analyzed to investigate the correlation between the endoscopic finding and the invasion level. The creeping lesions were excluded from this analysis because of lack of the correlation between the size and the level of invasion in this type (12). Since the characteristic endoscopic findings of submucosa-invasive colorectal carcinoma have been reported to include impression of tenseness, easy bleeding, white coating (erosion), white spots, and abnormal micro vessels (14-23), a logistic regression analysis for the each finding was performed between the minimally and massively submucosa-invasive lesions (Table 3). Interestingly, impression of tenseness was only the statistically significant (p<0.05) endoscopic finding to predict massively submucosa-invasive carcinoma. The tenseness was used for the lesions which had less mobility (within 2 mm) when pushed by an forceps. These lesions also had less transformation of the shape during air insufflation. Other endoscopists have expressed tenseness as solid impression (14, 15), stiffness (18, 22), or expansiveness (14, 24).

Logistic regression analysis for Isp/Is and depressed colorectal carcinoma
To decide indications of endoscopic resection for the Isp/Is and the depressed colorectal carcinoma, the other logistic regression analysis of the 187 resected lesions (162 intramucosal or minimally submucosa-invasive and 25 massively submucosa-invasive; 151 Isp/Is and 36 depressed) was performed using the size and shape as variables. We found that the possibility (P) of minimally submucosa-invasive carcinoma can be predicted using the following logistic regression analysis:

1
P=-----------------------------------
1+exp (-0 -jxj)

(0: constant, j: partial regression coefficient of xj, xj: explanatory variable of No. j)

where the shape variables were defined using the following grid: Shape
variable : Isp/Is depressed
X1 : 0 1

1
P =------------------------------------------------------------------
1+exp[-4.09313- (-2.0926x1 - 0.105465size)]

The confidence intervals of the analysis were shown in Table 4.

For example, for a 20 mm depressed lesion,

1
P=-------------------------------------------------------------
1+exp[-4.09313- (-2.0926 1 - 0.105465 20)]

1 1
=----------------------- = --------------------- = 0.4728342
1+exp (0.10877) 1+1.1149059


therefore, the possibility that the lesion would be minimally submucosa-invasive is 47%.
Possibilities of minimal invasion to the submucosal layer were calculated using the present logistic regression analysis for different sizes of the Isp/Is and the depressed colorectal carcinoma lesions (Table 5). Because the prior probability of this analysis was 87% (162 intramucosal or minimally submucosa-invasive lesions / 187 all lesions), the lesion whose possibility is less than 87% should be considered massively submucosa-invasive.

Discussion
This study was designed to endoscopically distinguish the intramucosal and minimally submucosa-invasive colorectal carcinoma from the massively submucosa-invasive one in order to avoid the unwarranted endoscopic resection for the massively invasive lesions. For this purpose, the histologic types, the macroscopic findings (size and shape), the endoscopic findings, and the invasion levels of 330 early colorectal carcinoma resected endoscopically or by laparotomy in our and satellite hospitals were analyzed. We also performed two different logistic regression analysis to investigate the correlations of the invasion level to the endoscopic finding (for 41 submucosa-invasive lesions), and the size (for 187 Isp/Is and depressed lesions), respectively.
Histologically, we found that the proportion of massive invasion to the submucosal layer in all the well-differentiated adenocarcinoma lesions was only 3.9% (12/305), whereas that in the moderately-differentiated, poorly-differentiated, signet ring cell or mucinous adenocarcinoma was over 50% (Table 1). Further, while no lymph node metastasis was found in the well-differentiated adenocarcinoma lesions (0/305), 9.5% (2/21), 50% (1/2), and 100% (1/1) of the metastasis were detected in the moderately differentiated, signet ring cell, and mucinous adenocarcinoma lesions, respectively. These results indicate that only the well-differentiated colorectal adenocarcinoma lesions are suitable targets for endoscopic resection. Many recent reports have demonstrated that well-differentiated colorectal adenocarcinoma is less likely to invade to the submucosal layer and accompany with lymph node metastasis than other histologic ones (6, 25-28). For example, Egashira et al. (29) have histologically analyzed 44 surgically resected colorectal adenocarcinoma invading to the submucosal layer, and found that predominant moderately-differentiated adenocarcinoma showed significantly deeper submucosal invasion than predominant well-differentiated one (29). They also reported that the positive rate of lymph node metastasis in predominant moderately-differentiated adenocarcinoma tended to be higher than that in predominant well-differentiated one. These reports may confirm our data about the correlation between the histologic type and invasion level of early colorectal carcinoma.
Since our results showed that any size of the IIa colorectal carcinoma lesions as well as all of the creeping and the almost Ip ones less than 20 mm in size were not massively submucosa-invasive (Table 2), it is likely that these lesions can be treated with endoscopic resection when they are well-differentiated adenocarcinoma. Our data could be supported by Kudo et al. (11) and Terai et al. (30) who reported that no or few massively submucosa-invasive carcinama were found in the Ip and the IIa type colorectal carcinoma in any size. The creeping colorectal tumors are also reported to have laterally-spreading growth tendency without invasion to the submucosal layer (13, 31, 32). Conversely, our results demonstrated that the rate being massively submucosa-invasive in the Isp/Is and the depressed lesions increased in a size-dependent manner (Table 2), so that the logistic regression analysis in the present study may support the decision of the treatment way for these lesions (Table 5). Because the prior probability of this analysis was 87% (162 intramucosal or minimally submucosa-invasive lesions / 187 all lesions), the colorectal carcinoma lesion whose possibility is less than 87% is likely to be massively submucosa-invasive. According to the results in Table 5, all of the depressed lesions and the Isp/Is ones over 20 mm in size are likely to be massively submucosa-invasive, and they should be treated with laparotomy. This analysis was chosen in this study because the variable (size) was irregular distribution. When the variable is regular, a discriminant analysis can be also used.
To further support the endoscopic distinction between minimally and massively submucosa-invasive colorectal carcinoma, we investigated the correlation between the endoscopic finding and the invasion level of the carcinoma using the other logistic regression analysis, and found that only impression of tenseness, but not easy bleeding, white coating, white spots, or abnormal microvessels is the finding predicting massively submucosa-invasive one (Table 3). This finding may be useful when a treatment plan (endoscopic resection or laparotomy) for the equivocal cases, especially the Isp/Is colorectal carcinoma lesions, is decided. Our results could be supported by the reports from Oda et al. (24) and Tamura et al. (33) who also asserted that this endoscopic finding is a good sign for colorectal tumors with massively submucosal invasion.
In conclusion, our findings in this study suggest that the early colorectal well-differentiated adenocarcinoma lesions which belongs to the IIa type in any size, and the creeping or Ip type less than 20 mm in size, are suitable targets for endoscopic resection. Conversely, other histologic type lesions should be resected by laparotomy. The logistic regression analysis in this study suggests that all of the depressed and the Isp/Is lesions over 20 mm in size should be also treated with laparotomy. This analysis technique also suggests that the endoscopic finding, impression of tenseness, may be a helpful sign predicting massively submucosal invasion, especially in the equivocal cases.

Acknowledgement
We thank Dr. Koji Nagahara in Koseiren Bisai Hospital and Dr. Kazuo Goto in Gifu Prefecture Tajimi Hospital for their great help to collect materials. We also thank Mr. Norio Sugimoto (Sanwa Kagaku Co. Ltd., Nagoya, Japan) for his great help to analyze our data.

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Nagoya City University
Medical School