Tumor Cell Implantation from an Oral Advanced Cancer at the Rectal Endoscopic Submucosal Dissection Site: A Case Report and Literature Review

Abstract

This report and literature review explores cases of tumor cell implantation at colorectal post-endoscopic resection sites. We detail a unique case in which advanced rectosigmoid colon cancer cells would implant into an endoscopic submucosal dissection (ESD) site in a synchronous upper rectal colon intramucosal cancer. The patient underwent upper rectal ESD prior to surgery for the advanced rectosigmoid colon cancer. After 7 months, a follow-up colonoscopy revealed recurrence at the upper rectal ESD scar, and the patient underwent Miles' operation. The recurrence was confirmed by RAS mutation status to be implantation from the advanced rectosigmoid colon cancer.

The literature review, encompassing ten cases, shows that implantation often occurs at rectal post-endoscopic resection sites, with some cases associated with nearby advanced cancers, particularly on the oral side. Four cases suggested implantation from cancer during ESD. These findings underscore the need for caution during colorectal ESD procedures, considering the potential implantation risk. Additionally, early detection of implantation and subsequent curative resection were common outcomes, suggesting the importance of vigilant surveillance. Further research and preventive measures such as thorough intraluminal lavage and complete closure of ulcers may be crucial in minimizing implantation risks post-endoscopic treatment.

Introduction

Tumor cell implantation commonly occurs at the anastomotic site after surgery for colorectal cancer[1]. Postoperative implantation has been thought to be due to exfoliated tumor cells at the time of surgery[1,2]. Although implantation by percutaneous endoscopic gastrostomy was previously widely reported in the endoscopic field, implantation is very rare after endoscopic resection of superficial colorectal tumors[3]. However, with the increase in endoscopic treatment, especially endoscopic submucosal dissection (ESD), there have been several reports of implantation in recent years[4,5]. These cases were considered to have been caused by implantation of tumor cells during the endoscopic resection procedure. We report a unique case of tumor cell implantation from an advanced rectosigmoid cancer at the ESD site of a synchronous upper rectal intramucosal carcinoma. In addition, because it is not well described, we searched the literature for previous implant cases after colorectal endoscopic resection and performed a literature review to extract their characteristics for monitoring.

Case Report

A man in his 60s was referred to our hospital for treatment of locally advanced cancer and a lateral spreading tumor (LST). A colonoscopy showed a 40-mm-diameter LST in the upper rectal colon with large nodules and type 2 advanced rectosigmoid colon cancer in the oral side of approximately 10 cm (Figure 1A, 1B, 1C, 1D). The LST had an irregular large nodule, and we assumed that there was slight submucosal invasion of the cancer at the nodule. Therefore, we performed ESD for upper rectal colon LST ahead of surgery for advanced rectosigmoid colon cancer (Figure 2A). Histopathological examination of the en bloc resected ESD specimen sectioned at 2-mm intervals showed an intramucosal adenocarcinoma with adenomatous components and tumor-free resection margins around the entire circumference of the tumor with no evidence of lymphovascular invasion and budding grade 1. We then performed laparoscopic sigmoidectomy with lymph node resection for advanced rectosigmoid colon cancer. Histopathological examination showed moderately differentiated adenocarcinoma, pT3, int, INFb, ly1, v2, pN1 (1/33) pStage IIIA, pPM0 (60 mm), pDM0 (40 mm), pRM0.

Figure 1.

(A) Colonoscopy findings. A 40-mm-diameter laterally spreading tumor in the upper rectum colon. (B) En bloc resected specimen. (C) Colonoscopy findings. Type 2 advanced rectosigmoid colon cancer. (D) The resected specimen showing a 55 × 40 mm tumor.

Figure 2.

(A) Colonoscopy findings. Post-endoscopic submucosal dissection (ESD) ulcer. (B, C) Colonoscopy findings. Local recurrence at the ESD scar with a large polypoid mass and anastomotic site (yellow arrow). (D) The resected specimen showing a 30 × 15 mm tumor. The anastomotic site (yellow arrowhead) was found 30 mm oral side from the tumor and ESD scar.

Surveillance colonoscopy was performed 7 months later and revealed local recurrence at the upper rectal ESD scar with a large polypoid mass (Figure 2B, 2C). The patient underwent Miles' operation for this rectal carcinoma, considering post-ESD and postoperative scarring and adhesions. Histopathological examination showed moderately differentiated adenocarcinoma, pT2, int, ly0, v0, pN0 (0/5), pStage I, pPM0 (55 mm), pDM0 (17 mm), pRM0 (Figure 2D). Because it was suspected that the lesion was an implantation onto the post-ESD ulcer, we examined the mutational status of the RAS genes in the upper rectal ESD specimen, first rectosigmoid surgical specimen, and second upper rectal surgical specimen. The first surgical specimen and second surgical specimen were concordant (Table 1). This indicated that the upper rectal recurrence lesion was implanted from the advanced rectosigmoid colon cancer.

Table 1.

Mutational Status of RAS Genes in Surgical Specimens of the Patient.

Genes	Codon	First rectosigmoid surgical specimen		Recurrence of upper rectal surgical specimen	Upper rectal ESD specimen
KRAS	12				G12A
	13	G13D		G13D
	59
	61
	117				K117N
	146
NRAS	12
	13				G13R
	59
	61
	117
	146
		Negative		Positive

RAS: Rat sarcoma; ESD: Endoscopic submucosal dissection; KRAS: Kirsten rat sarcoma viral oncogene homolog; NRAS: Neuroblastoma RAS viral oncogene homolog

Discussion

We experienced a case of strongly suspected tumor cell implantation from an advanced rectosigmoid colon cancer at the ESD site of a synchronous upper rectal colon intramucosal carcinoma. We demonstrated that recurrent lesions in post-ESD scars had a concordant mutational status of RAS genes with advanced colorectal cancer on the oral side but not with ESD lesions. Several mechanisms that are common in colorectal cancer surgery are thought to cause implantation in post-ER ulcers. More than 100 years ago, the possibility that exfoliated cancer cells could implant the wound was reported by Ryall et al.[2]. It is well known that exfoliated tumor cells are present in the colonic lumen of patients with colorectal cancer[1]. These exfoliated cancer cells have the ability to implant[6]. Intraluminal transplantation of exfoliated rectal cancer cells is known to be one of the mechanisms of anastomotic recurrence after rectal surgery, and intraoperative washout before anastomosis is recommended[1], which we also performed in this case.

However, because implantation after colorectal endoscopic resection is not well known, we searched the literature for previous case reports and extracted their characteristics for monitoring. A PubMed database search was performed using the terms ((((rect*[tiab]) OR (colon*[tiab])) OR (colorect*[tiab])) AND (((((ESD[tiab]) OR (EMR[tiab])) OR (“endoscopic submucosal dissection”[tiab])) OR (“endoscopic mucosal resection”[tiab])) OR (“endoscopic mucosal resection”[Mesh]))) AND ((implantation[tiab])) up to December 2023, and six articles were retrieved[3-5,7-9]. We also searched Ichushi-Web (Japan Medical Abstracts Society; http://www.jamas.or.jp/about/english.html) databases using the same query terms in Japanese, and two articles were retrieved[10,11].

Including our report, ten lesions in nine patients showed implantation after colorectal endoscopic resection. Of these patients, five were male and four were female, with a median age of 70 (52-86) years. The lesions (suspected implantation sites) that underwent endoscopic resection were in the rectum in seven cases, sigmoid colon in two cases and cecum in one case. The median tumor size was 29 (5-155) mm, and the resection method was ESD in nine cases and EMR in 1 case (Table 2). The median time of recurrence owing to implantation was 12.5 (7-74) months. Six cases, including our case, appeared to be transplanted from advanced cancer in the nearside, five had advanced cancer on the oral side[3,8,10,11], and one had advanced cancer on the anal side[11]. Also, four cases were implanted to a rectal post-endoscopic resection ulcer from oral side advanced cancer[3,8,10]. In all six of these cases, surgical resection of advanced cancer was performed after endoscopic resection. Although one case had advanced cancer in the oral side, it finally demonstrated to be from an ESD lesion[9]. Since this case was deeply invasive (2000 μm) submucosal carcinoma, the possibility of recurrence due to vascular invasion was also mentioned, although vertical and lateral margins were negative[9]. The other three implantation cases were thought to have occurred during endoscopic resection[4,5,7]. The implanted lesions were surgically treated in nine cases[3-5,8,9] and ESD-treated in one case[7], all of which were curative resections. One case of surgical resection resulted in recurrence again 2 years later, resulting in best supportive care[10].

Table 2.

Characteristics of Implantation Lesions.

Case	Age (years old)	Gender	Endoscopic resection (Implantation) site	Tumor size (mm)	Endoscopic procedure method	Location synchronous advanced cancer	Median time of implantation (month)	Treatment for implantation lesion
1*	63	Male	Rectal colon	40	ESD†	Rectosigmoid colon	7	Surgery
2 (9)	86	Male	Sigmoid colon	9	ESD	Cecum	12	Surgery
3 (8)	70	Female	Rectal colon	20	ESD	Sigmoid colon	20	Surgery
4 (7)	71	Female	Rectal colon	155	ESD	None	15	ESD
5 (5)	62	Male	Rectal colon	74	ESD	None	13	Surgery
6 (4)	52	Male	Rectal colon	65	ESD	None	74	Surgery
7 (3)	61	Female	Rectal colon	5	EMR	Rectosigmoid colon	12	Surgery
8 (10)	70	Male	Rectal colon	28	ESD	Rectosigmoid colon	24	Surgery
9 (11)	74	Female	Sigmoid colon	20	ESD	Transverse colon	11	Surgery
10‡ (11)	74	Female	Cecum	30	ESD	Transverse colon	11	Surgery

*: Our case; ^†: endoscopic submucosal dissection; ^‡: Same case as 9.

Although one case cannot be ruled out of recurrence due to deep submucosal invasion[9], four cases, including our case, showed concordant KRAS mutations[3,8] and the other case showed concordant copy number variation (CNV) analysis[9], which explained the implantation. The remaining six cases were diagnosed as implantation on the basis of circumstantial evidence. In our case we detected a KRAS G13D mutation in both sigmoid cancer and recurrent lesion. Matsunaga et al. reported that KRAS G13D mutation rate was significantly higher in patients with anastomotic recurrence and hypothesized that the KRAS G13D mutant may have an enhanced adhesion ability to the extracellular matrix and migration[12]. RAS mutations have been extensively studied and clinically validated as biomarkers for predicting responses to targeted therapies. Therefore, analyzing RAS mutations can directly inform treatment decisions and improve patient outcomes. CNV analysis can capture genome-wide copy number variation and provide insight into multiple genetic alterations across different regions of the tumor. In the future, combining both approaches may allow for a more comprehensive understanding of the disease and better informed clinical decisions.

The findings of this review are that six of the ten cases, including ours, were thought to have been implanted from nearby advanced cancers[3,8,10,11], especially from the oral side. In addition, seven cases were implanted in rectal post-endoscopic resection ulcers[3-5,7,8,10] and four of these cases, including ours, involved implantation from oral side advanced cancer[3,8,10]. Generally, because feces are temporarily stored in the rectum, cancer cells may also stagnate in the rectum and easily implant in post-endoscopic resection ulcers. In contrast, one case was implanted from advanced cancer on the anal side into oral ESD site[11]. The authors mentioned the possibility of implantation at post-ESD ulcer sites on the oral side of advanced cancer due to multiple insertion of colonoscopes. However, this would not be unexpected because it has been pointed out that implantation can also occur during colonoscopy via the working channel of the endoscope[13].

In the present review, three cases were without advanced cancer at the nearby site[4,5,7]. These cases were considered to have been caused by implantation of tumor cells during the ESD procedure. In addition, although one case had advanced cancer in the oral side, it was demonstrated to be originated from an ESD lesion by CNV analysis[9]. It is thought that after colorectal ESD, a large number of tumor cells exfoliate into the intestinal lumen. ESD requires complex endoscopic maneuvers and takes time, which may have damaged the tumor and exfoliated tumor cells in these four cases[4,5,7,9]. Of course, incomplete resection that leaves residual tumor is a recognized cause of local recurrence after endoscopic resection. However, in almost all cases in this review, the tumors were resected en bloc and R0 resection was obtained, so it is unlikely that there were any residual tumors, and it is reasonable to consider it as an implanted tumor. In addition, although one case cannot be ruled out of recurrence due to deep submucosal invasion[9], molecular pathological evidence of implantation was obtained in four of the ten cases in this review, including our case, strongly suggesting implantation[3,8,9].

Another new finding is that most of the implants were detected within 1 year, and curative resection was achieved with subsequent endoscopic or surgical treatment. Although transplant lesions are considered to show rapid progression[7], many of the cases in this review could be curatively resected with early detection. To prevent implantation after endoscopic treatment, it is important to perform the resection in a way that damages the tumor as little as possible. Matsuda et al. showed in a meta-analysis that intra-operative rectal washout is useful for the prevention of local recurrence in rectal cancer surgery[1]. Sufficient intraluminal lavage is also desirable in colorectal ESD. However, in the present review, there were four cases of implantation at endoscopic resection sites of rectal tumors in which there was advanced cancer on the oral side. In such cases, it is considered that implantation is caused by exfoliated cancer cells from advanced cancer on the oral side; therefore, washout is thought to be ineffective. To prevent this, it may be useful to close the ulcer completely with a clip or another device after washing out. Furthermore, if the target lesion for ESD is unlikely to be diagnosed as cancer, prior surgical treatment of advanced cancer may be a good way to prevent implantation. Either way, analyses of further cases will be necessary to minimize the risk of implantation.

In conclusion, we experienced a case in which implantation of exfoliated tumor cells from an oral advanced cancer at a rectal ESD site was strongly suspected. Similar cases have been reported, and caution is recommended for rectal ESD regarding transplantation when accompanied by oral advanced cancer.

Conflicts of Interest

There are no conflicts of interest.

Author Contributions

Conception and design: Takeshi Yamashina and Masaaki Shimatani; drafting the article: Takeshi Yamashina and Masaaki Shimatani. Revising it critically for important intellectual content: Hironao Matsumoto, Masahiro Orino, Masataka Kano, Natsuko Saito, Shunsuke Horitani, Toshiyuki Mitsuyama, Masahiro Takeo and Takafumi Yuba; Final approval of the version to be published: Takeshi Yamashina, Masaaki Shimatani, Hironao Matsumoto, Masahiro Orino, Masataka Kano, Natsuko Saito, Shunsuke Horitani, Toshiyuki Mitsuyama, Masahiro Takeo and Takafumi Yuba.

Approval by Institutional Review Board (IRB)

The Ethics Committees of Kansai Medical University Medical Center (No. 2021304)

Informed Consent

Ethical approval was obtained from the patient for the publication of this case report.