Undetermined Margins After Colonoscopic Polypectomy for Malignant Polyps: The Need for Radical Resection

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1 Undetermined Margins After Colonoscopic Polypectomy for Malignant Polyps: The Need for Radical Resection EUN-JOO JUNG 1, CHUN-GEUN RYU 1, JIN HEE PAIK 1 and DAE-YONG HWANG 1,2 1 Department of Surgery, Colorectal Cancer Center, Konkuk University Medical Center, 2 Konkuk University School of Medicine, Seoul, Republic of Korea Abstract. Aim: The aim of the present study was to analyze the clinicopathological features of patients with colorectal cancer (CRC) who underwent radical operation after malignant polyp removal by colonoscopic procedure. Patients and Methods: Between 2009 and 2013, radical colorectal resection was performed in 50 patients with CRC after colonoscopic polypectomy. Results: Nine cases (18%) had residual cancer. Lymph node (LN) metastasis was found in three cases (6.0%) and tumor deposit without LN metastasis (N1c) was found in two cases (4.0%). The indications for radical operation were an undetermined resection margin (23 cases), positive lateral margin (15 cases). Out of the nine cases with residual cancer, five cases had LN metastasis or tumor deposit without residual tumor in the main lesion. One-fourth of cases with an undetermined margin had residual cancer (six out of 23 cases), three of whom had stage III disease. Conclusion: Undetermined may be considered as an indication for additional radical operation. As the incidence of colorectal cancer (CRC) is increasing worldwide, screening colonoscopy is frequently performed (1, 2). With instrumental and technical development in colonoscopy, colonoscopic procedures, including polypectomy, endoscopic mucosal dissection (EMR), and endoscopic submucosal dissection (ESD), are commonly performed for colorectal polyps (1-4). In particular, for patients who are diagnosed with CRC after colonoscopic procedures, further radical surgery could Correspondence to: Dae-Yong Hwang, MD, Ph.D., Department of Surgery, Colorectal Cancer Center, Konkuk University Medical Center, Konkuk University School of Medicine, ,120-1, Neungdong-ro, Gwangjin-gu, Seoul, Republic of Korea. Tel: , Fax: , hwangcrc@kuh.ac.kr Key Words: Colon polyp, colorectal neoplasm, endoscopic mucosal resection, polypectomy. be needed, according to the pathological results (2-4). These include positive resection at polypectomy, poorly differentiated histological type, deep submucosal invasion, and the presence of lymphovascular invasion, which are the well-known high-risk factors for lymph node metastasis and residual cancer (2-4). In patients with these risk factors, additional radical colorectal surgery is recommended for oncological safety (2-4). However, the presence of residual cancer after radical surgery is reported in fewer than 11-15% of patients (2). We often receive a pathological report stating undetermined after colonoscopic procedures. Surgeons are concerned about how they can translate this report and whether further radical operation is required or not. Considering the incidence of residual cancer in patients with definite high-risk factors, we were concerned that radical operation may be an over-treatment. Moreover, there exist few reports on the treatment guidelines for undetermined after colonoscopic procedures for CRC. Therefore, the aims of this study were to analyze the clinicopathological findings of patients with CRC who underwent radical operation after tumor removal by endoscopic procedure, and to assess the clinical characteristics of patients with undetermined after colonoscopic procedures. Patients and Methods Patients. From the prospectively collected database of patients with CRC, a total of 50 cases were enrolled which underwent radical colorectal operation after tumor removal by endoscopic polypectomy between January 2009 and September Endoscopic procedures included EMR, ESD, or polypectomy. Indications for radical surgery were as follows: positive resection, deep submucosal invasion greater than 1 mm, presence of lymphovascular invasion, or poorly differentiated cellular type. Undetermined, when the resection margin could not be evaluated clearly, was considered as the indication for operation in this study. Patients who underwent transanal excision for early rectal cancer were excluded from this study /2015 $

2 Table I. Patients characteristics. Characteristic N=50 Age (mean, years) 58.8±11.0 (22-77) Gender (male: female) 33:17:00 Incidence of preoperative CEA elevation 0 Incidence of preoperative CA19-9 elevation 0 Colon: rectum 35:15:00 Tumor location Ascending colon 10 Hepatic flexure 1 Transverse colon 2 Descending colon 1 Sigmoid colon 21 Recto-sigmoid junction 10 Upper rectum 5 Operation Right hemicolectomy 12 Transverse colectomy 1 Left hemicolectomy 2 Anterior resection 24 Low anterior resection 11 Operation-related morbidity included Dindo-Clavien classification grade III-V. Statistical analysis. Data analysis was performed using SPSS version 17.0 for Windows (SPSS Inc., Chicago, IL, USA). Results In total, 50 cases, consisting of 33 males and 17 females (mean age=58.8 years, range=22-77 years), were included in this study. Preoperative serum levels of carcinoembryonic antigen (CEA) or carbohydrate antigen (CA) 19-9 were not elevated in all cases. The characteristics of the patients are shown in Table I. The indications for further radical surgery are presented in Table II. The most common indication was undetermined in 23 cases (46%), when the resection after colonoscopic procedure could not be evaluated accurately, followed by positive in 15 cases (30%). After radical colorectal surgery, residual cancer was detected in nine cases (18%). The mean size of the tumor was 1.2 cm and mean number of retrieved lymph nodes was 15.6 (range=7-50). In most cases, the cellular type was well- or moderately-differentiated, but two cases had poorly differentiated tumor cells. There were few T2 lesions (6%). In terms of the N stage, most cases had no lymph node metastasis, but 5 cases (10%) had lymph node metastasis. There was no postoperative morbidity or mortality. The pathological profiles of the cohort are shown in Table III. Table II. Indications for radical surgery after colonoscopic procedure. Indication No. of cases * Undetermined 23 (46%) Positive 15 (30%) Invasion depth >1 mm 7 (14%) Lymphatic invasion 5 (10%) Poor differentiation 2 (4%) * A few cases had multiple risk factors for the residual tumor. Comparing the incidence of residual cancer and TNM stage, of the 23 cases with undetermined, six (26.1%) had residual cancer, and this proportion was higher than that in the group (11.1%) with established indications (p=0.017). In the distribution of TNM stage, the proportion of patients with stage III CRC was significantly higher in the group with undetermined (13.0%) than in the group with traditional indications (7.4%) (p=0.043). The clinicopathological features of nine cases with residual cancer in the resected colorectal specimen after radical operation are shown in Table IV. The last five cases (55.5%) had stage III disease. In particular, although there was no residual tumor in the colonic wall in case numbers 6 and 8, tumor deposit and two metastatic lymph nodes were found in the pericolic area. Discussion In our study, the incidence of residual cancer was 18%, and the incidence of stage III disease was 10.0% in patients who underwent curative resection after colonoscopic polypectomy. Undetermined were the most common indication for further radical surgery, and 26.1% of patients with undetermined were found to have residual cancer. In another study, with similar indications for further radical surgery, the incidence of residual cancer was reported to be about 2-11% (2, 5, 6), which is lower than that in our study. The incidence of locoregional lymph node metastasis was also higher in our study (10%) than in other studies (4-7%) (2, 5, 6). Regarding the indications for further radical surgery after endoscopic procedure for malignant colorectal polyp, most published reports suggest positive margin at polypectomy, poorly differentiated histological type, deep submucosal invasion, and the presence of lymphovascular invasion (2, 5, 7-11). These are high-risk factors for residual tumor, lymph node metastasis, and recurrence (3-5). T1 cancer has been associated with regional lymph node metastasis in 7-15% of patients (5, 8, 12, 13). Kudo divided the depth of submucosal invasion of sessile polyps 6888

3 Jung et al: Undetermined Margin After Colonoscopic Polypectomy Table III. Pathological features after surgery. Characteristic N=50 Residual tumor (+) 9 (18.0%) Tumor size (cm) 1.2±0.6 ( ) Cellular differentiation Well-differentiated 15 (30.0%) Moderately differentiated 33 (66.0%) Poorly differentiated 2 (4.0%) No. of retrieved lymph nodes 15.6±11.1 (7-50) T-Stage Tis 11 (22.0%) T1 36 (72.0%) T2 3 (6.0%) N-Stage N0 45 (90.0%) N1 3 (6.0%) N1c 2 (4.0%) Final TNM stage Stage 0 11 (22.0%) Stage I 34 (68.0%) Stage III 5 (10.0%) into: Sm1, invasion within the upper third of the submucosa (<300 μm from the muscularis mucosa); Sm3, with more than two-thirds of the submucosa invaded; and Sm2, intermediate level (14). The degree of submucosal invasion is a risk factor for lymph node metastasis in CRC, in particular for Sm3 (6, 12). Other studies reported that the risk of lymph node metastasis was 1-3% in Sm1, 8% in Sm2, and 23% in Sm3 cancer (6, 12). Based on these data, additional radical resection is recommended for Sm2 and Sm3 lesions of CRC after polypectomy (6, 16). Our results show why radical resection is needed for Sm2 lesions. Case 6 in Table IV had an Sm2 lesion with clear resection margin after polypectomy. Further colorectal resection was performed because of Sm2 invasion. In the final pathological report, tumor deposit was found without residual tumor in the colonic wall, and finally, this was T1N1cM0, stage III. This patient received adjuvant chemotherapy with FOLFOX regimen, and is alive without recurrence or metastasis. The treatment for patients with undetermined is not yet established (5). In many articles on endoscopic treatment for malignant colorectal polyp, undetermined, or unknown were not analyzed in detail, and were only mentioned briefly (2, 5). Butte et al. suggested that an unknown margin status could be considered with positive or close resection because the inability to evaluate the margin is associated with Table IV. Clinicopathological features of individual patients with residual cancer after surgery. No. Sex/ Indication Operation Tumor TNM Final age, years for surgery type size stage (cm) 1 M/52 Undetermined AR 0.9 T1N0M0 I 2 M/65 Undetermined AR 1.5 T2N0M0 I 3 M/66 Deep (+) LAR 1.8 T2N0M0 I 4 F/60 Undetermined RHC 0.4 TisN0M0 0 5 M/55 Undetermined AR 1.5 T1N1aM0 III 6 M/69 SM2 with LAR 0.5 T1N1cM0 III clear 7 F/56 Poorly AR 1.1 T1N1bM0 III differentiated type Lateral (+) Lymphovascular invasion (+) 8 M/53 Undetermined AR 0.8 T1N1bM0 III 9 M/53 Undetermined AR 2.5 T2N1cM0 III AR: Anterior resection, LAR: low anterior resection, RHC: right hemicolectomy. piecemeal resection or poor specimen orientation (2). Piecemeal polypectomy for malignant polyp is considered as incomplete resection and is a risk factor for residual cancer; therefore, further excision or surgical resection is required (6, 15, 17, 18). Boenicke et al. mentioned that snare polypectomy of malignant polyps could be effective and safe but polypectomy artifacts make it difficult for pathologists to evaluate the resection margin of sessile polyps (5, 11). In several studies on colonoscopic polypectomy, the incomplete resection rate was reported to be about % (17, 19). This incompleteness of removal is related to piecemeal resection and poor ability of endoscopy (17, 19). Pathological reports of incomplete resection could be presented as positive resection or unknown. Incomplete resection may be related to poor ability of endoscopy (17, 19). Undetermined could be evidence of piecemeal polypectomy (2, 11, 17, 20). In our study, an undetermined margin status was chiefly reported in polypectomy specimens obtained from outside clinics Interestingly, compared to other indications for further radical surgery, the group with undetermined had higher incidence of residual cancer and lymph node 6889

4 metastasis. Undetermined could also be a negative factor for lymph node metastasis (5). In other words, overlooking the undetermined margin is a type of undertreatment, and causes locoregional recurrence and distant metastasis in the long-term follow-up. Considering that the incidence of absence of residual tumor is almost 82%, few surgeons have been concerned that further radical resection might be overtreatment (21). However, even their study, they obtained unassessable resection after a colonoscopic procedure in 40% of the patients and residual cancer in 30% (21). Therefore, we should measure the oncologicai benefit for the 20% of patients with residual cancer and operation-related risk for the 80% of patients without residual cancer. With the development of surgical technique and instruments, operation-related mortality and complication rates are decreasing remarkably (6). Benizri et al. reported that the severe surgical complication rate (Dindo-Clavien classification grade III-V) was 12.5% in patients who underwent radical colorectal surgery after colonoscopic polypectomy, with complications including intraabdominal abscess, wound hematoma, anastomotic leakage, pulmonary embolism, myocardial infarction, and hemoperitoneum (6). However, in our study, there were no severe complications, although minor complications (Dindo-Clavien classification grade I-II) were reported, including atelectasis, wound infection, and ileus. For an experienced surgeon, oncological benefit is an important issue compared to operation-related risks. There is a limitation to our retrospective study due to the rather small sample size. Only patients who underwent colonoscopic polypectomy followed by radical colorectal resection were enrolled in the study. Most polypectomies were performed at outside clinics, and only representative slides were reviewed at our Hospital. In summary, undetermined after an endoscopic procedure for malignant colorectal polyp are reported commonly. Patients with undetermined resection had a higher incidence of residual tumor and lymph node metastasis. Therefore, an accurate assessment of the resection after colonoscopic polypectomy is important for deciding the treatment plan, and awareness of the clinical significance of undetermined could avoid undertreatment of colorectal cancer. In conclusion, undetermined resection after colonoscopic polypectomy could be considered as an additional indication for further radical colorectal surgery. This factor could be helpful in improving the oncological outcome of CRC. Conflicts of Interest The Authors declare no potential conflicts of interest. References 1 Hong YS, Jung EJ, Ryu CG, Kim GM, Kim SR, Hong SN and Hwang DY: Incidence and multiplicities of adenomatous polyps in TNM stage I colorectal cancer in Korea. 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