The Effect of Preceding Biopsy on Complete Endoscopic Resection in Rectal Carcinoid Tumor

Patients and inclusion criteria

We reviewed retrospectively the records of patients with rectal subepithelial tumor who had undergone an endoscopic treatment at Konkuk University Hospital (Seoul, Korea), during a 7-yr period from July 2005 to July 2012. The data gathered on the patients and procedures were through endoscopic images, review of chart, and histologic results.

To be eligible for inclusion, the tumors had to be located in the rectum and be less than 20 mm in diameter. The endoscopic treatments which were included in the study were endoscopic submucosal dissection (ESD), endoscopic mucosal resection-band ligation (EMR-L), and conventional snare polypectomy. We excluded tumors resected by other methods, including hot biopsy, argon plasma coagulation (APC) and cold biopsy. Depending on the histological results, well-differentiated neuroendocrine tumors (grade I or II), namely carcinoid tumors, were included and other tumors were excluded. The tumors which involved muscularis propria, adjacent vessels, lymph nodes, or distant organ were additionally excluded. The cases with inadequate medical records were excluded as well. For patients with multiple rectal carcinoid tumors, each tumor removed by endoscopic treatment was categorized as a separate case.

Probable risk factors for incomplete tumor resection

According to completeness of resection, each tumor was classified into clear resection margin group (A group) and positive margin group (B group). When both the lateral and deep margins were free of tumor cells, it was denominated as complete resection. If it was unclear whether resection margin was involved, it was included in the positive margin group, as the subsequent therapeutic plan would be similar.

Probable risk factors for incomplete tumor resection were as follows: preceding biopsy before endoscopic resection; size of the tumor measured by endoscopist; location of tumor; morphology of tumor; and method of endoscopic treatment. In addition, we investigated the depth of invasion and whether endoscopic ultrasonography (EUS) was performed.

The location of tumor was divided into proximal and distal part of the rectum. Distal rectum was defined as the rectum located below the second valve of Houston. We used the diameter as measured by endoscopist during endoscopy rather than the diameter of specimen measured by pathologist, as part of the mass may have been removed by preceding biopsy. Also, in the positive resection margin group, a small portion of the residual tumor may have still remained on the resection site. Therefore the size of specimen as measured by pathologist may be smaller than the actual size.

The endoscopic morphology of tumor was divided into three types: protruded type; slightly elevated or flat type; and depressed or ulcerative type (Fig. 1). If biopsy was taken before the endoscopic resection, morphology after the preceding biopsy was selected as a risk factor of incomplete resection, as morphology of tumor may be transformed by biopsy. Describing tumor according to the Parris-Japanese classification, protruded type belonged to Ip, Isp and Is lesions, slightly elevated or flat type belonged to IIa and IIb lesions and depressed or ulcerative type were IIc and III lesions.

Fig. 1
Color and endoscopic morphology of rectal carcinoid tumor. Among the 98 cases, tumors were yellow in 85 cases, white and pale in 10 cases, and the other three cases were similar in color to the surrounding normal mucosa. Tumor morphology after biopsy was classified into protruded type in 51 cases, slightly elevated or flat type in 43 and depressed or ulcerative type in 4. (A) The tumor is white and pale and morphologically belonged to the protruded type. (B) The color of tumor is yellow and it is of the slightly elevated type. (C) In the C-1 image, the tumor is a depressed type, and the color is neither yellow nor white. It could not be easily distinguished from the surrounding mucosa, but the tumor had definite capillary bed. C-2 image was the same patient's endoscopic image before the biopsy was taken. It shows typical features of carcinoid tumor, which was yellow-colored and slightly elevated type.

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The endoscopic treatments were classified into three methods: ESD, EMR-L and conventional snare polypectomy. Simplified ESD which performed submucosal dissection with snaring was included in the ESD method.

Review of endoscopic records

In order to determine if carcinoid tumors were distinguished by endoscopy, we searched for the endoscopic records at the time of diagnosis. If the patient was referred from another hospital, we additionally reviewed the medical treatment request and endoscopic images of the previous hospital. Then we investigated whether "carcinoid" was written in the medical records before the patient was histologically confirmed to carcinoid tumor. In addition, we reviewed the records of patients who had rectal subepithelial tumor during the same study period and investigated the cases where the rectal tumor was recorded as "carcinoid" on medical record, but in fact were not.

We also reviewed the endoscopic images to see whether the shape and color of tumor were typical and if it looked like a subepithelial lesion, macroscopically. Review of the images was performed by two experienced endoscopists. If there were differing views, an agreement was reached through a discussion.

Endoscopic procedure

Standard colonoscope (CF-H260; Olympus, Tokyo, Japan) was used for the procedure. The colon was cleansed with 4 L polyethylene glycol electrolyte solution. Midazolam (Dormicum®) for conscious sedation and meperidine (Demerol®) for pain control were selectively given to patients. The procedure was performed in a standard fashion by one endoscopist and one assistant, and tumor removed following a saline injection mixed with indigocarmine and epinephrine. Conventional snare polypectomy was performed using oval-shaped snares (Olympus, Tokyo, Japan). Band ligation method was performed by standard upper endoscope (GF-260; Olympus) and pneumo-activate ELV device (Sumitomo Bakelite Co., Ltd., Tokyo, Japan). ESD was mostly carried out using a dual knife (KD-650L; Olympus).

Statistical analysis

Continuous variables were summarized as mean±standard deviation (SD), and categorical variables as frequency (%). To analyze the risk factors of incomplete tumor resection, categorical data were compared using chi-square or Fisher's exact tests. Then, we used logistic regression analysis to estimate the odds ratio (OR) and 95% confidence interval (CI) of risk factors that caused incomplete tumor resection. All analyses were conducted using SPSS for Windows (versions 19.0). A P value of less than 0.05 was considered statistically significant.

Ethics statement

The study was approved by the institutional review board of Konkuk University School of Medicine which confirmed that the study was in accordance with the ethical guidelines of the Helsinki Declaration (KUH1010502). All patients provided written consents to undergo endoscopic treatment and were informed of the risks and potential benefits of the procedures.

Characteristics of patients and tumors

Over the 7-yr period studied, 5,235 patients had undergone colonoscopic polypectomy, EMR or ESD in our unit. Among the patients, 113 patients were diagnosed with rectal subepithelial tumor and 16 of them were not carcinoid tumor. Therefore we identified 97 patients with rectal carcinoid who had undergone endoscopic tumor resection. There were three cases with no tumor in the resected tissue by endoscopic resection, although preceding biopsy revealed a carcinoid tumor. It may be that the small tumor was almost entirely resected by biopsy forceps, when the biopsy was performed. These three cases were excluded from the study, as they were not treated by the prescribed methods and the resection margin status could not be identified. In five patients, carcinoid tumor was found simultaneously at more than two locations. Four of these patients had two concurrent rectal carcinoids, and the other had one rectal carcinoid and one ampulla of Vater carcinoid. Thus, a total of 98 cases (94 patients) were finally included for the study (Fig. 2). The overall mean age and tumor size were 48.04±11.12 (range 29-75) yr and 7.40±2.86 (range 3-15) mm, respectively. Other characteristics of the tumors are shown in Table 1.

Fig. 2
Selection of the cases. A total of 5,235 patients underwent endoscopic treatment of colonic tumor (polypectomy, EMR or ESD) at our hospital, during a 7-yr period from July 2005 to July 2012. Among them, we identified 113 patients with subepithelial tumor on rectum who had undergone endoscopic tumor resection. Finally, 98 rectal carcinoid cases (94 patients) were included, and the resection margin was clear in 57 cases.

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Table 1
Baseline characteristics of the patients and tumors

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Comparison of group A and B

The clear resection margin group (A group) and the positive margin group (B group) had 57 and 41 cases, respectively (Table 2). The B group included six cases where the margin status was unclear. Thirty five cases with definitely positive resection margin were composed of 18 deep margin positive cases, 1 lateral margin positive case, 2 both margin positive cases and 14 cases which were not marked separately.

Table 2
Probable risk factors for incomplete resection of rectal carcinoid tumor and comparison of group A and B

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The mean age of the A group was 49±12 (range 29-75) yr, and the mean tumor size was 7.26±2.83 (range 3-15) mm in diameter. The mean age of the B group was 47±10 (range 29-68), and the mean tumor size was 7.59±2.90 mm (range 3-15). A previous biopsy had been performed in 26 cases (45.6%) in group A and 31 cases (75.6%) in group B.

In group A, 21 (36.8%) tumors were removed by ESD, 28 (49.1%) tumors resected by snare polypectomy and 8 (14.0%) were EMR-L. In group B, ESD, snare polypectomy and EMR-L were performed in 13 (31.7%), 25 (61.0%) and 3 (7.3%) cases, respectively.

Tumor morphology before biopsy was divided into 57 protruded types and 39 slightly elevated or flat types. There was no depressed or ulcerative type. Two cases were not evaluated due to poor endoscopic images. However, tumor morphology after biopsy was changed into 51 protruded types, 43 slightly elevated or flat types, and 4 depressed or ulcerative types. Lesions confined to the mucosal layer were 2 in group A and 1 in group B. The rest had submucosal invasion. In both A and B groups, EUS was performed in 15 cases for each group. Of these several risk factors, only preceding biopsy was significantly associated with the risk of incomplete tumor resection (P=0.004, chi-square tests, Table 2). Logistic regression analysis revealed that patients who were performed preceding biopsy were about 3.7 times more likely to fail to completely remove tumors as compared to patients with naïve lesions (OR, 3.696; 95% CI, 1.528-8.938; P=0.004).

Identification of carcinoid tumor by initial endoscopy

All 98 carcinoid cases were observed as subepithelial lesion by the endoscopic images. Eighty five cases were yellow-colored tumor and ten cases were white and pale. Only three cases were similar in color to the surrounding normal mucosa. There were five cases which had definite capillary bed on tumor (Fig. 1). In all cases without biopsy and in 53 out of the 57 cases with preceding biopsy, "carcinoid" was written in the initial medical records before tumor was histologically confirmed as carcinoid. There were no unevaluated cases due to lack of the initial endoscopic record. Therefore, in 95.9% (94 cases) of all cases, carcinoid tumor could be suspected by macroscopic appearance at the time of the initial endoscopic examination.

There were five cases where the endoscopist attempted to remove the tumor with biopsy forceps, carcinoid tumor was not suspected at the time. In three of these cases, there was no residual tumor in the specimen obtained by additional polypectomy, and they were excluded from our study as stated earlier. The other two cases came under the four cases where "carcinoid" was not written in the initial medical records.

In three cases, although a preceding biopsy did not reveal a carcinoid tumor, a polypectomy was done from a strongly suspected carcinoid tumor macroscopically. These three cases were all diagnosed with carcinoid tumor, finally.

There were 16 patients who had rectal subepithelial tumor excepting carcinoid tumor in the study period. The histologic results were as follows: chronic nonspecific inflammation, inflammatory polyp, hyperplastic polyp, lymphoid polyp, leiomyoma, lipoma and malignant lymphoma (Fig. 2). Among these, according to the initial endoscopic records, there were six patients where the tumor looked like rectal carcinoid, but were not. None of the cases underwent EUS, and the final histologic results showed chronic nonspecific inflammation in three patients, lymphoid polyp in one, lipoma in one, and hyperplastic polyp in one (Fig. 3).

Fig. 3
Rectal subepithelial tumors mimicking carcinoid tumor. There were six patients with tumor which looked to be rectal carcinoid, but were not. The final histologic results showed chronic nonspecific inflammation in 3 patients (A-C), lymphoid polyp (D), lipoma (E) and hyperplastic polyp (F). All of these patients did not undergo EUS. The retrospective review of the images showed that image C and F did not look like a subepithelial lesion.

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Follow-up

In the B group, an evaluation was performed by patient's medical record from the timing of the polypectomy to October 2013. There has been no recurrence within the follow-up period and one patient underwent a surgical operation (lower anterior resection) due to the carcinoid tumor. Only 24 out of 41 patients were properly monitored. Their mean follow-up period was 33.29±24.75 (range 12-95) months and a first follow-up endoscopy and imaging studies were performed at 7.25±6.42 (range 2-24) months after the procedure. In one patient, follow-up study was performed at four months after the procedure, and then the patient did not visit the hospital for six years. The remaining 16 patients did not visit our outpatient gastroenterology clinic after the procedure. Two of them underwent health examination in our hospital after two and seven years, respectively, and there was no relapse.