Indication for Endoscopic Resection of Submucosal Colorectal Carcinoma: Special Reference to Lymph Node Metastasis

We investigated the relationship between histological factors and lymph node metastasis in 77 lesions with submucosally invasive colorectal carcinomas to establish useful criteria for lesions in which endoscopic treatment alone results in cure of malignancy. There were positive correlations between histological factors, including the level of invasion, the histologic grade, presence or absence of lymphatic invasion, presence or absence of budding, and lymph node metastasis (p < 0.05, p < 0.05, p < 0.005, p < 0.01). The presence or absence of venous invasion did not influence lymph node metastasis. Laparoscopic surgery involving lymph node dissection should be indicated for sm1 carcinoma lesions with unfavorable histological factors. In lesions diagnosed as sm2 or sm3 prior to resection, intestinal resection involving lymph node dissection by laparoscopic surgery should be directly performed without endoscopic resection. In treating submucosally invasive colorectal carcinomas, the level of invasion can be clinically diagnosed, consequently endoscopic resection should be initially performed when lesions are evaluated as sm1 prior to resection. When histological investigation reveals sm1 carcinoma with histologic grade I (well-differentiated) or II (moderately-differentiated), and the absence of lymphatic invasion and budding, endoscopic treatment alone is sufficient.


11][12][13][1
][15].In particular, since endoscopic mucosal resec- tion (EMR) was developed, superficial-type carci- noma lesions have been easily and completely Corresponding author.Tel." + 81-942-31-7561.Fax: +81-942-34-2623.E-mail" tsuruta@med.kurume-u.ac.jp.

resected.Currently, endoscopic resection is most commonly performed in patients with early colo- rectal carcinoma [16][17][18][19][20].

On the other hand, laparoscopic surgery has gen- erally been performed as minimally invasive surgery for colorectal carcinoma [21][22][23][24].Currently, it is   recommended that lapar scopic surgery should not be indicated for Dukes B or C lesions with serosal invasion, since port site recurrence may occur.However, it is indicated that laparoscopic surgery with- out the risk of port site recurrence should be indicated for Dukes A lesions, which invade the proper muscle layer or a more superficial site [25,26].This procedure, differing from the standard endo- scopic resection procedure, is characterized by a capacity for curative resection in lesions with lymph node metastasis, since this procedure facilitates lymph node dissection.

Therefore, endoscopic treatment is not indicated for Dukes A lesions, which invade the muscularis propria.Among carcinoma lesions that invade the submucosal layer, some cases are ndicated for endoscopic treatment with radical purpose of cura- bility, while laparoscopic surgery should be aggres- sively performed on lesions in which lymph node metastasis may occur.In this study, to establish useful criteria for lesions in which endoscopic treat- ment alone results in cure of malignancy, we exam- ined the relationship between histological factors and lymph node metastasis in patients with early colorectal carcinoma.


MATERIALS AND METHODS

In 77 submucosally invasive carcinoma lesions, the male-to-female ratio was 56:21.Mean patient ages were 62 + 9 years for males (47-85 years) and 65

11 years for females (
4-78 years).Overall, the mean age was 63 + 10 years.There was no significant dif- ference between males and females.Tumor sites included the sigmoid colon in 29 patients, the rectum in 16, the transverse colon in 12, the ascending colon in 12, the descending colon in 7, and the cecum in 1.

The surgical resection involving lymph nodes dissection was performed at the Department of Surgery, Kurume University Hospital, between April 1995 and March 1999.As the treatm nt for 77 lesions of submucosally invasive carcinoma, colectomy was initially performed in 58 lesions, and colectomy following EMR in 19 lesions.EMR is a procedure in which a lesion with the peripheral normal mucosa is snared and electrically resected after elevating the lesion from the submucosal layer by infusing physiological saline solution into the submucosal layer (Fig. 1).These 77 submucosally invasive carcinomas were evaluated histopathologically at the Department of Pathology of Kurume University Hospital.Submucosally invasive carci- nomas as defined for this study involved carcinomas infiltrating into the submucosal layer, but above the proper muscle layer.Gross appearance was classified into type I (protruding type) lesions, which include Ip (ped- unculated), Isp (subpedunculated), and Is (sessile) tumors, and type II (superficial type) lesions, which include IIa (superficial elevated type), IIb (super- ficial flat type), and IIc (superficial depressed type) tumors, according to the classification established by the Japanese Research Society for Cancer of the Colon and Rectum [27].However, IIb type was not found in the present patients.

Five histological parameters were evaluated as follows.

(1) Level of invasion: When colectomy was ini- tially performed, the submucosal layer was equally divided vertically i to three sections according to the classification descri ed by Kudo et al. [28], and the superficial layer was regarded as sml, followed by the middle sm2 and the deeper sm3.In lesions for which EMR was performed, the resected submucosal layer was equally divided vertically into two sections according to the classification of Tsuruta et al. [29].Carcinoma infiltration within one-half of the depth was regarded as sml, and that beyond one-half as sm2, and positive for vertical submucosal stump as sm3 (Fig. 2).This classifica- tion seems to be possible methodology for appro- priateness of determination of the invasive depth in comparing EMR specimen with colectomy specimen.(a) Optimal visualization and targeting of the lesion by endoscopy should be obtained before colonoscopic treatment.Needle forceps is used to puncture the mucosa near the lesion.(b) Physiologic saline solution is injected into the submucosa.The lesion is then elevated along with the surrounding mucosa.(c) A snare device is placed around the elevation. (d) The elevation is resected using cutting current only.(e) The resected specimen is then carefully catched by grasping forceps and withdrawn.

(2) Histologic grade: Histologic grade was deter- mined by the least differentiated area of the infiltra- tion site according to the criteria ofthe World Health Organization [30], and classified as grade I, II, or III.

Well-differentiated adenocarcinoma was classified as grade I; moderately-d fferentiated adenocar- cinoma as grade II; and poorly-differentiated ade- nocarcinoma, including signet ring cell carcinoma and mucinous adenocarcinoma as grade III.

(3) Lymphatic invasion: Lymphatic invasion was determined by the resence of tumor cells in the lumen covered with endothelial cells in the absence of erythrocytes.

(4) Venous invasion: Venous invasion was de er- mined by the presence of tumor cells in the lumen where endothelial cells covered with the smoo h muscle with elastic laminae, as detected by elastica van Gieson staining, were present.

(5) Budding: Budding was determined by the presence of cancer nests c

sisting
f 5 or fewer tumor cells as described by Morodomi et al. [31].

The size of lesions was measured by macroscopy or dissecting microscopy of the resected specimens.

These data were statistically analyzed by Student's t-test, Fisher's exact test, chi-square test, or Mann-Whitney U-test.p < 0.05 was regarded as significant.


RESULTS

With respect to gross appearance, 12 lesions were classified as Ip, 21 lesions as Isp, 2 lesions as Is, carcinoma scularis submucosa sml A sm3 submucosa resection margin muscularis propria Surgical Specimen EMR Specimen FIGURE 2 Classification of the level of invasion of submucosal invasive carcinoma.The submucosal layer was equally divided vertically into three section, the superficial layer was egarded as sml, followed by the middle sm2 and the deeper sm3 in the case of surgical specimen.In lesions for which EMR was performed, the resected submucosal layer was equally divided vertically into two sections, carcinoma infiltration within one-half as sm2, and positive for vertical submucosal stump as sm3.(3-30mm), respectively.There was a significant difference in size between type I (Ip, Isp, and Is) and type IIc (p < .05) (Table I).

Treatment was examined with respect to the level of invasion.Of 19 sml lesions, colectomy alone was performed in 14 lesions, while colectomy following EMR was performe in 5 lesions.Of 27 sm2 lesions, colectomy alone was performed in 15 lesions, while colectomy following EMR was performed in 12 lesions.Of 31 sm3 lesions, colectomy alone was performed in 29 lesions, while colectomy following EMR was perfo med in 2 lesions.

Lymph Node Metastasis Related to Histological Parameters (Table II) Lymph no e metastasis was detected in 13 (16.9%) of the 77 lesions of the submucosally invasive car- cinoma examined.

Level of Invasion While no lymph node metas- tasis was detected in the 19 sml lesions, lymph node metastasis was detected in 4 (14.8%) of the ENDOSCOPIC R SECTION OF COLORECTAL CANCER 105 27 sm2 lesions, and 9 (29.0%) of the 31 sm3 lesions.

There was a significant difference in metastasis with respect to level of invasion (p < 0.05).

Grade III Carcinoma Lymph node metastasis was detected in 9 (13.0%) of 69 lesions of grade I or I carcinoma.Lymph node metastasis was detected in 4 (50.0%) of 8 lesions of grade III carcinoma.There was a significant difference with respect to grade (p < 0.05).

Lymphatic Invasion While lymph node metas- tasis was detected in 6 (9.8%) of 61 lesions without lymphatic invasion, it was detected in 7 (43.8%) of 16 lesions with lymphatic invasion.There was a significant difference in metastasis with respect to lymphatic invasion (p < 0.005).

Venous Invasion Lymph node metastasis was

etected in 10 (18.5%) of 54 lesions withou
venous invasion.Lymph node metastasis was detected in 3 (13.0%) of 23 lesions with venous invasion.There as no significant difference in metastasis with respect to venous invasion.Budding Lymph node metastasis was detected in 2 (5.0%) of 40 lesions without budding and in 11 (29.7%) of 37 lesions with budding.There was a significant difference in metastasis with respect to budding (p < 0.01).


Level of Invasion R lated to Histological

Parameters (Table III) Nineteen lesions were classified as sml, 27 lesions as sm2, and 31 lesions as sm3.

Grade III Carcinoma While one sml lesion (5.3%) was classified as grade III carcinoma, one sm2 lesion (3.7%) was classified as grade III carcinoma, and six sm3 lesions (19.4%) were classified as grade III carcinoma.There was no significant difference in grade be ween the three levels of invasion (p < 0.086).

Lymphatic Invasion One sml lesion (5.3%), three sm2 lesions (11.1%), and 12 sm3 lesions (38.7%) were positive for lymphatic invasion.O. TSURUTA et al.

T

rameter bet
een sm, sm2, and sm3 (p < 0.005).


CASE PRESENTATION

This is a 66-year-old male with submucosal carci- noma in the sigmoid colon.

The lesion was resected by EMR (Fig. 1).Pre- operative findings by chromoendoscopy and bar- ium enema study were shown in Fig. 3(a) and (b).

EMR specimen showed sm2, Grade II, negative lymphatic invasion, negative venous invasion and negative budding (Fig. 3(c)).Lymph node metas- tasis was found (Fig. 3(d)).


DISCUSSION

Protruding lesions can be endoscopically resected by flexible endoscopic polypectomy, which was initially reported by Wolff and Shinya [32].How- ever, it was difficult to completely resect superficial- type lesions by this procedure.EMR [16][17][18][19] has facilitated complete resection of superficial-type lesions involving the submucosal layer and periph- eral normal mucosa.For this reason, currently, endoscopic resection is aggressively indicated for all macroscopic early colorectal carcinoma lesions.

However, there is a complicating issue.When carcinoma tissues invade the submucosal layer, lymph node metastasis is detected in some lesions.Many studies have reported lymph node metastasis from submucosally invasive carcinoma.As factors, the level of invasion, histologic grade, presence or absence of lymphatic invasion, presence or absence of venous invasion, and presence or absence of budding have been indicated 1,2,4-11,13-15].

With respect to the level of invasion, Haggitt's classification [4] is commonly used in Europe and the United States.According to this classi ication, protruding carcinoma lesions are classified into pedunculated lesions and sessile lesions.In pedun- culated lesions, the level of submucosal invasion is classified into four grades.Lesions infiltrating the polyp head are evaluated as Level 1. Lesions infil- trating the neck are evaluated as Level 2. Lesions infiltrating the stalk are evaluated as Level 3.

Lesions infiltrating the intestinal wa l submucosal layer below the stalk are evaluated as Level 4.

Most lesions with lymph node metastasis are evaluated as Level 4.Many studies have indicated that intestinal tract resection by laparotomy involv- ing lymph node dissection is required in Level 4 lesions [4,6,9,13].Macroscopically, it has been reported that all sessile lesions invading the sub- mucosal layer correspond to Level 4, and that intes- tinal tract resection by laparotomy involving lymph node dissection is required in all sessile submucosally invasive carcinoma lesions [4,6,9,13].However, Nivatvongs et al. [9] described that the incidence of lymph node metastasis in sessile sub- mucosally invasive carcinoma lesions was lower than that in pedunculated submucosally invasive carcinoma lesions (10%, 27%), which is different issue from previous report, although both lesions demonstrated Level 4 i vasion.This difference might be explained by the nature of Haggitt's classification itself, that is, the sessile type lesion includes wide variety of carcinoma tissue invasion to the submucosal layer, but pedunculated type lesion has massive invasion as the Level 4 [4].In this study, we used the classification of the invasion level, which may correlate with the level of invasion to the submucosal layer regardless of the gross appearance.There was a correlation between the level of invasion and lymph node metastasis (p < 0.05).Our classification of the invasion level may be more useful than Haggitt's classification from the perspective of availability for all gross appearance.

As for histologic grade and lymphatic invasion, there is a widely accepted concept that they have close relation to lymph node metastasis.Venous invasion is ontroversial as an affect- ing factor on lymph node metastasis, while bud- ding in histologic findings is described as a factor to influence lymph node metastasis in the textbook edited by Japanese Research Society for Cancer of the colon and rectum.

With respect to the histologic grade, lymphatic invasion, venous invasion, and budding other than the level ofinvasion, there were positive correlations between histological factors, including the histo- logic grade, lymphatic invasion, budding, and lymph node metastasis (p < 0.05, p < 0.005, p < 0.01).The presence or absence of venous inva- sion did not statistically influence lymph node metastasis, which is different from previous report.This may have been because veins were more accurately identified by elastica van Gieson staining in this study, differing from previous studies employing hematoxylin and eosin (H.E.) staining alone.

These results suggest that histological criteria for lesions in which endoscopic treatmen alone results in cure of malignancy indicate sml invasion, histo- logic grade I or II, and the absence of lymphatic invasion and budding [33].

Indication for additional colectomy after EMR must stand on strict criteria based on the histologic factors in the sml lesions.When the lesions were found to be sm2 or sm3 following EMR, they must have surgery because of the great possibility of lymph node metastasis significantly suggested by the presence of multiple unfavorable histologic factors.

If histological factors can be evaluated prior to endoscopic resection, surgery may be directly performed wit out unnecessary endoscopic resec- tion in lesions requiring surgery.Furthermore, in some specimens collected during endoscopic resec- tion, histological factors cannot be sufficiently evaluated due to heat degeneration related to cauterization during resection.It is not appropriate to determine whether laparot