Predictive Factors of Positive Circumferential and Longitudinal Margins in Early T3 Colorectal Cancer Resection

M. Ashraf Balbaa; Noha Elkady; Emad M. Abdelrahman

doi:10.1155/2020/6789709

Predictive Factors of Positive Circumferential and Longitudinal Margins in Early T3 Colorectal Cancer Resection

Balbaa, M. Ashraf;Elkady, Noha;Abdelrahman, Emad M. 2020-06-27 00:00:00 Hindawi International Journal of Surgical Oncology Volume 2020, Article ID 6789709, 8 pages https://doi.org/10.1155/2020/6789709 Research Article Predictive Factors of Positive Circumferential and Longitudinal Margins in Early T3 Colorectal Cancer Resection 1 2 3 M. Ashraf Balbaa , Noha Elkady , and Emad M. Abdelrahman General Surgery Department, Faculty of Medicine, Menouﬁa University, Menouﬁa 32511, Egypt Pathology Department, Faculty of Medicine, Menouﬁa University, Menouﬁa 32511, Egypt General Surgery Department, Faculty of Medicine, Benha University, Benha 13511, Egypt Correspondence should be addressed to M. Ashraf Balbaa; ashraf_balbaa@hotmail.com Received 8 February 2020; Accepted 3 June 2020; Published 27 June 2020 Academic Editor: C. H. Yip Copyright © 2020 M. Ashraf Balbaa et al. )is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. Malignant involvement of circumferential resection margin (CRM) and longitudinal resection margin (LRM) after surgical resection of colorectal cancer (CRC) are associated with higher rates of recurrence and development of distant metastasis. )is can inﬂuence the overall patient’s prognosis. )e aim of the current study was to identify pathological factors as predictors for the involvement of resection margins in early T3 CRC. Patients and Methods. Fifty patients radiologically diagnosed to have cT3a/ b (CRC) were included in the study. After resection, the pathological examination was performed to identify patients with positive CRM and/or LRM. Relations between the diﬀerent pathological parameters and the CMR and LRM involvements were assessed. Results. Positive CRM was present in 17 cases (34%), while positive LRM was found in 6 cases (12%). )e involvement of both margins was signiﬁcantly associated with rectal tumors and tumors with inﬁltrative gross appearance, grade III, deeper invasion, and positive lymph node metastases. Also, there was a signiﬁcant association between both margins’ positivity and other pathological parameters as signet ring carcinoma, tumor budding, perineural and vascular invasion, high microvessel density (MVD), and sinusoidal vascular pattern, while the presence of necrosis and inﬁltrative advancing tumor front was signiﬁcantly associated with CRM involvement only. )e depth of tumor invasion and signet ring carcinoma were identiﬁed as independent predictor factors for positive CRM and LRM, respectively. Conclusion. Preoperative identiﬁcation of these pathological pa- rameters can be a guide to tailor the management plan accordingly. resection margin (CRM) as well as longitudinal resection 1. Introduction margin (LRM) can be considered the hallmark of a suc- Globally, Colorectal Cancer (CRC) is the third most com- cessful oncologic resection [5]. Many studies have dem- monly diagnosed cancer and the second cancer-related onstrated that CRM involvement is able to predict local th leading cause of death [1]. In Egypt, it occupies the 7 recurrence and poor prognosis among patients with rectal as among all cancers, where it represents 3.47% and 3% of well as colon cancer [5–7]. On the other hand, the LRM cancers in males and females, respectively [2]. Currently, the positivity has been shown to be a predictor for local re- treatment strategy for CRC patients involves a multimodal currence, development of distant metastasis, and decreased approach based on tumor-related characteristics and pa- disease-free survival [8–10]. In spite of conﬁning to standard tient-related factors [3]. However, surgery remains the surgical rules to achieve grossly negative resection margin mainstay curative treatment for patients with nonmetastatic (R0), still, positive resection margins are detected micro- CRC and the quality of surgical procedure can signiﬁcantly scopically on postoperative histopathological examination inﬂuence both short- and long-term disease outcomes [4]. [5, 11, 12]. )is can be clearly demonstrated in early T3 One of the crucial pillars of surgical quality is achieving tumors where surgery is the main line of therapy. For colon negative resection margins. Negative circumferential cancer, guidelines recommend neoadjuvant therapy to be 2 International Journal of Surgical Oncology ensure grossly free CRM of the rectum by sharp and precise used only in selected cases of T4 and not for T3 tumors [13, 14]. For rectal cancer, although NCCN guidelines [15] dissection at the anatomical fascial planes. Great care has been taken to avoid injury of the hypogastric nerve. recommend neoadjuvant therapy for T3 tumors, still ESMO guidelines [16] recommend neoadjuvant therapy for Labeling and orientation of the specimens were per- tumors> cT3b as a routine therapy and for cT3a/b tumors in formed before sending to the Pathology Department at the conditioned indications [17]. We assume that pathological Faculty of Medicine, Menouﬁa University. Surgical speci- features indicating rapidly dividing, inﬁltrative, and ag- mens were grossly examined to assess tumor site, size, and gressive tumors have an association with positive margins. gross appearance. Hematoxylin and Eosin (H&E) stained )e aim of this study was to explore the pathological factors slides were histologically examined using light microscopy as predictors for the involvement of resection margins of to conﬁrm the diagnosis. Identiﬁcation of diﬀerent tumor early T3 CRC. If these factors can be recognized preoper- pathological ﬁndings was performed, including histopath- ological type, grade, depth of invasion, and lymph node atively, intraoperative modulation of surgical techniques and/or the addition of other therapeutic modalities can be involvement. Special tumor characters had been evaluated as the presence of tumor-associated inﬂammation, desmo- applied. plasia, budding, necrosis, mitotic and apoptotic indices, perineural and vascular invasion, microvessel density 2. Patients and Methods (MVD), vascular pattern, and the pattern of advancing )is study included 50 radiologically selected patients to be tumor front. Special attention was paid to determine CRM cT3a/b tumors out of 196 cases of operable CRC that were and LRM involvement. )e circumferential margin was not candidates for neoadjuvant therapy. )e patients have deﬁned as the shortest distance measured from the mi- been operated upon at Surgery Departments of the Main croscopically deepest area of tumor inﬁltration to the stained Hospitals of Menouﬁa and Benha Universities, during the CRM. Positive CRM involvement was deﬁned as tumor presence in a distance ≤1 mm from the nonperitonealized period from January 2016 to May 2019. An approval to conduct the research was obtained from both institutes’ surface of resection or by serosal penetration of the peri- tonealized portions of the colon [18]. )e LRM was deﬁned ethical and research committees (No# 12/2015 SURG 7 and 0134-12/15). A written informed consent was obtained from as the distance from the tumor edge to the closest resection all included patients. Exclusion criteria included patients margin(s). Resection margin of 2 cm was considered ade- with locally advanced tumors with evidence of local inﬁl- quate [18]. tration to other organs or surrounding tissue cT3 c/d or T4 According to the involvement CRM, patients were di- or those who have been operated upon in emergency sit- vided into two groups (CRM-positive and CRM-negative uations, as perforated or obstructed cases. Metastatic cases groups). )e same was performed according to LRM in- and operable ones after receiving neoadjuvant therapy were volvement (LRM-positive and LRM-negative groups). Re- excluded as well. Detailed history has been obtained from all lations between the diﬀerent pathological ﬁndings and the CMR and LRM involvements were assessed. patients. Systematic physical examination was performed followed by full preoperative investigations, including co- Statistical analysis was performed using SPSS-20 (Statistical Package for Social Sciences version 20). Uni- lonoscopy and biopsy as well as complete metastatic workup. All biopsies were histologically conﬁrmed to be CRC. MRI variate analysis was performed to identify signiﬁcant for rectal cancer was performed to select patients with cT3a/ predictors of a positive CRM and positive LRM. Qualitative b. Spiral CT for colon cancer was performed to select T3 parameters were expressed as the frequency with per- tumors that extend to the pericolic tissue but not to adjacent centage rates and the Chi-square test was used to assess the organs. It was demonstrated as thickening and inﬁltration of statistically signiﬁcant association. On the other hand, pericolic fat. Surgical resection was performed to all cases quantitative parameters were expressed as a range (mini- mum and maximum), mean, and standard deviation where after thorough intraoperative assessment of the non- metastatic stage of the tumors. Surgical resection included Student’s t-test and Mann–Whitney U test were used to assess the statistical signiﬁcance. )e crude odds ratios right hemicolectomy, left hemicolectomy, sigmoidectomy, anterior resection, and abdominoperineal resection. Colonic (OR) and their 95 percent conﬁdence intervals (95% CI) were calculated for each variable. Pathological parameters resection was performed with at least 5 cm longitudinal resection margins with excision of the adjoining mesentery associated with positive CRM and those with positive LRM that harbors all the tumor-draining lymph nodes. Proximal with a P value<0.05 were included in a multivariate logistic ligation of the arterial supply of the resected portion was regression to identify those variables that are indepen- performed to ensure harvesting all the draining lymph nodes dently associated with either positive CRM or positive with subsequent removal of adjoining devascularized bowel LRM, respectively. by this ligation. Circumferential resection included resection of the retroperitoneal adventitial tissue of the cecum, as- 3. Results cending, or descending colon. For the rectal resection, at least 2 cm of grossly free distal margin was obtained. Due to )e mean age of the included patients was 63.8 ± 4.1 years the proximal high ligation of the inferior mesenteric artery, with more incidence in males (31 cases; 62%) than females the proximal longitudinal margin was very abundant. )e (19 cases; 38%). Forty-one (82%) cases were diagnosed as principles of total mesorectal excision were followed to colon cancer while 9 (18%) cases were rectal cancer. International Journal of Surgical Oncology 3 Table 1: Distribution of the studied cases according to diﬀerent Twenty-three cases were grossly fungating type (46%). clinicopathological parameters (n � 50). Adenocarcinoma represented almost half of the cases (26 cases; 52%) and the others were either mucinous (15 cases; No. (%) 30%) or signet ring carcinoma (9 cases; 18%). Positive CRM Sex was present in 17 cases (34%), while positive LRM was found Male 31 (62%) in 6 cases (12%) (Table 1). Female 19 (38%) )e study showed that positive CRM was signiﬁcantly Age (years) associated with rectal location (P � 0.004), inﬁltrative gross Median (min.–max.) 63 (49–72) pattern (P � 0.005), signet ring carcinoma (P � 0.002), Mean± SD 63.8± 4.1 Site deeper tumor invasion (P< 0.001) (Figure 1), grade III Colon 41 (82%) tumors (P � 0.034), invasive pattern of advancing tumor Rectum 9 (18%) front (P � 0.002) (Figure 2), positive lymph node metastasis Size (P � 0.001), tumor budding (P � 0.016), presence of ne- Median (min.–max.) 4 (3–6) crosis (P � 0.029), perineural and vascular invasion Mean± SD 4.3± 1 (P � 0.04 and 0.021), high MVD (P< 0.001), and presence of Gross appearance sinusoidal vascular pattern (P � 0.001) (Table 2). Ulcer 15 (30%) On the other hand, the study showed a signiﬁcant as- Inﬁltrating 12 (24%) sociation between positive LRM and rectal location Fungating 23 (46%) (P � 0.007), inﬁltrative gross pattern (P � 0.049), signet ring Histopathological type carcinoma (P< 0.001) (Figure 3), deeper tumor invasion Adenocarcinoma 26 (52%) Mucinous 15 (30%) (P � 0.021), grade III tumors (P � 0.042), positive lymph Signet ring 9 (18%) nodes involvement (P � 0.01), tumor budding (P � 0.018), Depth perineural and vascular invasion (P � 0.009 and 0.011), high Pericolorectal tissue/serosa 20 (40%) MVD (0.004), and sinusoidal vascular pattern (P � 0.001) Muscularis propria 30 (60%) (Figure 4) (Table 2). Advancing tumor front Table 3 shows the univariate analysis of the diﬀerent Invasive pattern 37 (74%) pathological parameters and their relations with both pos- Broad pushing margin (cohesive pattern) 13 (26%) itive CRM and LRM. Multivariate logistic regression Desmoplasia 20 (40%) revealed that invasion of pericolorectal tissue/serosa was the Tumor budding 18 (36%) independent predictor factor for positive CMR (P< 0.001), Lymph nodes involvement 16 (32%) Inﬂammation 27 (54%) with the marginal signiﬁcance of inﬁltrative gross pattern Necrosis 19 (38%) (P � 0.055), while signet ring type was the independent Perineural invasion 5 (10%) predictor factor for positive LRM (P � 0.035) with the Vascular invasion 10 (20%) marginal signiﬁcance of high MVD (P � 0.53) and sinu- Tumor grade soidal vascular pattern (P � 0.54) (Table 4). G1 15 (30%) GII 17 (34%) 4. Discussion GIII 18 (36%) Mitotic index Presence of gross or microscopic evidence of malignant Median (min.–max.) 8 (1–11) tumor at the resection margins of CRC specimen is a Mean± SD 6.4± 3.1 Apoptotic index universally poor prognostic factor [19]. Previous studies Median (min.–max.) 9 (2–15) have concentrated on the CRM of the rectum as a very strong Mean± SD 7.7± 3.7 predictor of tumor recurrence. In a meta-analysis that in- MVD cluded over 17,000 patients, Nagtegaal and Quirke [20] were Median (min.–max.) 8 (2–18) able to demonstrate that involvement of CRM was a strong Mean± SD 7.7± 3.4 predictor of local recurrence (HR 2.7, 95% CI 1.7–4.3), Sinusoidal vascular pattern distant metastases (HR 2.8, 95% CI 1.9–4.3), and survival as Negative 39 (78%) well (HR 1.7, 95% CI 1.3–2.3). On the other hand, for the Positive 11 (22%) colon, LRM had great attention in research neglecting the Positive longitudinal resection margin 6 (12%) signiﬁcance of its radial margin. As demonstrated by Amri Positive circumferential resection margin 17 (34%) et al. [5], a cohort of nearly 1000 patients was essential to have enough statistical power to show the consequences of positive CRM of colon cancer. Believing in the signiﬁcance cancer [21] and resection of the retroperitoneal adventitial of both margins, CRM and LRM as predictors of the pa- soft tissue of the partially peritonealized colon [5]. Bujko tient’s outcome, the current study has explored diﬀerent et al. [22] demonstrated in their review that subclinical distal pathological factors that inﬂuence the positivity of both bowel intramural spread is present within 1 cm distally from resection margins in both colon and rectum. visible tumor edge in a considerable proportion of patients. )e key for the optimal CRM is the respect to the Consequently, for patients who are undergoing anterior embryonic fascia by total mesorectal excision for rectal resection for low-lying cancer, a distal bowel clear margin of 4 International Journal of Surgical Oncology compared with the previously reported prevalence in similar studies. Positive rates of CRM were reported to be 5.3% by Armi et al. [5], 17.6% by Kang et al. [26], 22% by Eriksen et al., and 28% by Birbeck et al. [27], while rates of positive LRM were reported to be 1.5% by Zeng et al. [10], 6.83% by Orosco et al. [28], and 7.9% by Kanters et al. [25]. In the current study, multivariate analysis has demon- strated that deeper tumor invasion up to the pericolorectal tissue/serosa was an independent predictor of positive CRM. )is observation is matching with Rickles et al. [11] and Warrier et al. [12] who demonstrated the signiﬁcant relation Figure 1: Positive circumferential margin in the case of mucoid between tumor “T” depth of invasion and positive CRM. )e carcinoma with signet ring diﬀerentiation (H&E 200). inﬁltrative gross pattern of tumors has been shown to have marginal signiﬁcance as an independent predictor as well. Although the results did not reach the statistical threshold of signiﬁcance, it seems that both parameters are coincident, as inﬁltrating tumor pattern is directly related to the depth of tumor invasion. In the previous studies [29, 30], it has been established that mucinous and signet ring types of CRC have a worse prognosis compared to other varieties of CRC. )ey are characterized by being prevalent in more advanced stages of the disease, with a much higher rate of lymphatic metastasis, serous inﬁltration, and peritoneal dissemination. In addi- tion, these two types of carcinomas have higher rates of the local extension, which leads to a lesser chance for curative resection and decreases the overall survival rate [31]. Signet Figure 2: Advancing tumor front (invasive type) in the case of ring carcinomas are considered high-grade adenocarci- high-grade adenocarcinoma (H&E 200). nomas. In these tumors, there is a loss of E-cadherin, cell adherence, tight junctions, and cell-cell interaction with the at least >1 cm is minimally acceptable. On the other hand, acquisition of stem cell-like characteristics leading to en- Hohenberger et al. [23] concluded in their study that the hanced tumor growth, invasion, and metastasis [32, 33]. standard LRM in colon cancer should be at least 5 cm on Obviously, the mucin provides pressure on the bowel wall with more tendency for tumor extension. On the other hand, both sides of the tumor. Conﬁning to these standards was performed during surgical resection in the current study. the intracellular mucin display may induce swelling of the tumor cells, due to its ability to imbibe water, and allow them Aggressive tumors are associated with uncontrolled cell proliferation and extensive invasion and metastasis. Un- to pass through the bowel layers with further dissemination [34]. )is coincides with our observations as it has been controlled proliferation is due to the activation of cell cycle genes and the loss of apoptosis-inducing ones and is re- shown that signet ring carcinoma was an independent ﬂected histologically as high mitotic and low apoptotic in- predictor for positive LRM in colorectal cancer. In a study by dices. While the ability for invasion is due to oncological Rickles et al. [11], they have demonstrated that signet ring metaplasticity and epithelial-mesenchymal transition where cell carcinoma and mucinous adenocarcinoma are inde- the cells lose adhesion and acquire cytoskeleton reorgani- pendent factors for CRM involvement. zation, contractility, and invadopodia and then become Neovascularization is an important factor in cancer growth and metastasis because it is involved in the capable of stromal invasion. )e advancing tumor front is one of the determinants of tumor invasion and in aggressive transport of various nutrients to the tumor cells [35]. Vascular changes in tumor areas are due to mediators tumors; it is usually an invasive pattern [24]. Positivity of the resection margins has been shown to be secreted by tumor cells or the surrounding microenvi- ronment. )e vascular patterns are either capillary-like or inﬂuenced by a lot of factors as tumor location, stage, grade, lymph node metastases, positive vascular and perineural sinusoid-like vessels which form a cobweb-like network invasion, and pattern of advancing tumor front and facilitate tumor invasion and metastasis [36]. [5, 11, 12, 25]. )e previously mentioned factors have been Microvessel density (MVD) has been documented to have demonstrated in the current study, in addition to other a prognostic value in colon cancer [37]. In the current pathological parameters that were signiﬁcantly associated study, MVD has been shown to have a marginal signiﬁ- with positive margins, such as signet ring carcinoma, tumor cance to be an independent predictor for positivity of the of LRM. )e limited number of included cases could be a budding, necrosis, high MVD, and ectatic vascular pattern. )e selection of higher “T” of the included cases within the factor that inﬂuenced the results and the statistical power threshold of signiﬁcance could have been reached if the present study may explain the encountered slightly higher rates of positive CRM (34%) and LRM (12%) when number of patients was quite larger. In the literature, we International Journal of Surgical Oncology 5 Table 2: Relation between circumferential and longitudinal resection margins and diﬀerent clinicopathological parameters (n � 50). Circumferential resection Longitudinal resection margin margin Test of sig. P Test of sig. P Negative Positive Negative Positive (n � 33) (n � 17) (n � 44) (n � 6) Sex Male 20 (60.6%) 11 (64.7%) 27 (61.4%) 4 (66.7%) 2 2 χ � 0.080 0.777 χ � 0.063 1.000 Female 13 (39.4%) 6 (35.3%) 17 (38.6%) 2 (33.3%) Age (years) 63.5 Median (Min.–max.) 63 (49–72) 66 (55–70) 63 (49–72) t � 0.507 0.615 (55–67) t � 0.792 0.432 Mean± SD. 63.5± 4.2 64.2± 4 63.9± 4.1 62.5± 4.5 Tumor site Colon 31 (93.9%) 10 (58.8%) 39 (88.6%) 2 (33.3%) 2 ∗ ∗ 2 ∗ ∗ χ � 9.374 0.004 χ �10.941 0.007 Rectum 2 (6.1%) 7 (41.2%) 5 (11.4%) 4 (66.7%) Tumor size Median (min.–max.) 4 (3–6) 4 (3–6) 4 (3–6) 4.5 (3–6) t � 0.376 0.709 t � 0.886 0.380 Mean± SD. 4.3± 1 4.4± 0.9 4.3± 0.9 4.7± 1.2 Gross appearance Ulcer 9 (27.3%) 6 (35.3%) 14 (31.8%) 1 (16.7%) 2 2 ∗ ∗ ∗ ∗ Inﬁltrating 4 (12.1%) 8 (47.1%) χ �10.448 0.005 8 (18.2%) 4 (66.7%) χ � 5.470 0.049 Fun gating 20 (60.6%) 3 (17.6%) 22 (50%) 1 (16.7%) Histopathological type Adenocarcinoma 23 (69.7%) 3 (17.6%) 25 (56.8%) 1 (16.7%) 2 2 ∗ ∗ ∗ ∗ Mucinous 7 (21.2%) 8 (47.1%) χ �12.624 0.002 15 (34.1%) 0 (0%) χ �13.543 <0.001 Signet ring 3 (9.1%) 6 (35.3%) 4 (9.1%) 5 (83.3%) Depth Pericolorectal tissue/serosa 3 (9.1%) 17 (100%) 15 (34%) 5 (83.3%) ∗ ∗ ∗ FE <0.001 χ � 5.35 0.021 Muscularis propria 30 (90.9%) 0 (0%) 29 (66%) 1 (16.7%) Tumor grade I 13 (39.4%) 2 (11.8%) 15 (34.1%) 0 (0%) 2 ∗ ∗ 2 ∗ ∗ II 12 (36.4%) 5 (29.4%) χ � 6.742 0.034 16 (36.4%) 1 (16.7%) χ � 5.685 0.042 III 8 (24.2%) 10 (58.8%) 13 (29.5%) 5 (83.3%) Advancing tumor front Invasive pattern 20 (60.6%) 17 (100%) 31 (70.5%) 6 (100%) 2 2 ∗ ∗ Broad pushing margin χ � 9.050 0.002 χ � 2.396 0.122 13 (39.4%) 0 (0%) 13 (29.5%) 0 (0%) (cohesive pattern) 2 2 ∗ ∗ ∗ ∗ Lymph nodes involvement 5 (15.2%) 11 (64.7%) χ �12.662 0.001 11 (25%) 5 (83.3%) χ � 8.257 0.010 2 2 Inﬂammation 15 (45.5%) 12 (70.6%) χ � 2.853 0.091 23 (52.3%) 4 (66.7%) χ � 0.440 0.674 2 2 Desmoplasia 11 (33.3%) 9 (52.9%) χ �1.797 0.180 16 (36.4%) 4 (66.7%) χ � 2.020 0.202 2 ∗ 2 ∗ ∗ Tumor budding 8 (24.2%) 10 (58.8%) χ � 5.824 0.016 13 (29.5%) 5 (83.3%) χ � 6.630 0.018 2 2 ∗ ∗ Necrosis 9 (27.3%) 10 (58.8%) χ � 4.741 0.029 15 (34.1%) 4 (66.7%) χ � 2.378 0.184 2 ∗ ∗ 2 ∗ ∗ Perineural invasion 1 (3%) 4 (23.5%) χ � 5.239 0.040 2 (4.5%) 3 (50%) χ �12.121 0.009 2 2 ∗ ∗ ∗ ∗ Vascular invasion 3 (9.1%) 7 (41.2%) χ � 7.219 0.021 6 (13.6%) 4 (66.7%) χ � 9.280 0.011 Mitotic index Median (min.–max.) 7 (1–11) 8 (2–10) 7 (1–11) 7.5 (4–10) U � 265.50 0.620 U � 97.50 0.311 Mean± SD 6± 3.2 6.4± 2.9 5.9± 3.1 7.5± 2.3 Apoptotic index Median (min.–max.) 7 (2–13) 10 (2–15) 9 (2–15) 7.5 (3–11) U � 207.50 0.132 U � 124.0 39.0 Mean± SD 7.2± 3.5 8.7± 4.1 7.8± 3.7 7.2± 3.9 MVD Median (min.–max.) 7 (2–13) 11 (7–18) 7 (2–18) 11 (10–11) ∗ ∗ ∗ ∗ U � 88.0 <0.001 U � 39.0 0.004 Mean± SD 6.3± 3 10.2± 2.5 7.3± 3.4 10.7± 0.5 Sinusoidal vascular pattern Negative 29 (87.9%) 10 (58.8%) 38 (86.4%) 1 (16.7%) 2 2 ∗ ∗ ∗ ∗ χ � 5.520 0.001 χ �14.947 0.001 Positive 4 (12.1%) 7 (41.2%) 6 (13.6%) 5 (83.3%) χ : Chi-square test; t: Student’s t-test; U: Mann–Whitney test; FE: Fisher’s Exact test; P: P value for association between negative and positive; : statistically signiﬁcant at P< 0.05. 6 International Journal of Surgical Oncology Figure 3: Signet ring carcinoma associated with positive longitudinal margin and creeping malignant cells beneath the intestinal glands (H&E 200). Figure 4: High-grade invasive adenocarcinoma associated with sinusoidal vascular pattern (H&E 200). Table 3: Univariate analysis for the clinicopathological parameters aﬀecting longitudinal and circumferential margins (n � 50). Longitudinal resection margin Circumferential resection margin P OR (95% CI) P OR (95% CI) Sex (male) 0.802 1.259 (0.208–7.638) 0.777 1.192 (0.353–4.018) Age (years) 0.427 0.924 (0.761–1.123) 0.607 1.039 (0.897–1.204) ∗ ∗ ∗ ∗ Tumor site (rectum) 0.005 15.60 (2.251–108.12) 0.007 10.850 (1.932–60.930) Tumor size 0.376 1.513 (0.605–3.781) 0.702 1.128 (0.609–2.088) ∗ ∗ ∗ ∗ Gross appearance (inﬁltrating) 0.021 9.0 (1.398–57.944) 0.010 6.444 (1.567–26.506) ∗ ∗ ∗ ∗ Histopathological type (signet ring) 0.001 50.0 (4.626–540.444) 0.032 5.455 (1.159–25.662) ∗ ∗ Tumor grade (Grade III) 0.030 11.923 (1.266–112.287) 0.019 4.464 (1.277–15.608) ∗ ∗ ∗ Depth (pericolorectal tissue/Serosa) 0.030 11.923 (1.266–112.29) <0.001 75.0 (11.291–498.196) Advancing tumor front 0.098 0.152 (0.016–1.411) 0.998 — Desmoplasia 0.174 3.50 (0.576–21.282) 0.184 2.250 (0.680–7.442) ∗ ∗ ∗ ∗ Tumor budding 0.030 11.923 (1.266–112.29) 0.019 4.464 (1.277–15.608) ∗ ∗ ∗ ∗ Lymph nodes involvement 0.018 15.0 (1.576–142.724) 0.001 10.267 (2.592–40.669) Inﬂammation 0.511 1.826 (0.303–11.020) 0.097 2.880 (0.827–10.034) ∗ ∗ Necrosis 0.143 3.867 (0.634–23.585) 0.033 3.810 (1.110–13.070) ∗ ∗ ∗ ∗ Vascular invasion (positive) 0.009 12.667 (1.888–84.965) 0.013 7.0 (1.515–32.333) Mitotic index 0.251 1.220 (0.869–1.713) 0.626 1.050 (0.863–1.277) Apoptotic index 0.705 0.956 (0.759–1.205) 0.171 1.125 (0.950–1.333) ∗ ∗ MVD (high) 0.042 1.401 (1.012–1.940) 0.001 1.731 (1.234–2.429) ∗ ∗ ∗ ∗ Sinusoidal vascular pattern 0.003 31.667 (3.133–320.06) 0.025 5.075 (1.223–21.065) OR: Odd`s ratio; CI: conﬁdence interval; #: all variables with P< 0.05 were included in the multivariate; : statistically signiﬁcant at P≤ 0.05. Table 4: Multivariate logistic regression (Forward: Wald) for circumferential and longitudinal resection margins. B SE Sig. OR Gross appearance (inﬁltrating) 2.371 1.285 0.055 10.713 Circumferential resection margin Depth (pericolorectal tissue/serosa) 4.590 1.172 <0.001 98.460 MVD (high) 0.679 0.351 0.053 1.972 Longitudinal resection margin Vascular pattern (sinusoidal) 3.780 1.961 0.054 43.820 Histopathological type (signet ring) 4.684 2.216 0.035 108.229 B: unstandardized coeﬃcients; OR: odds ratio; CI: conﬁdence interval; LL: lower limit. International Journal of Surgical Oncology 7 could not trace a similar model correlating the neo- References vascularization with positive involvement of CRC resec- [1] M. C. Wong, J. Huang, V. Lok et al., “Diﬀerences in incidence tion margins. However, in a study by Tarta et al. [38], they and mortality trends of colorectal cancer, worldwide, based on documented a signiﬁcant association between tumor high sex, age, and anatomic location,” Clinical Gastroenterology microvessel count and its depth of invasion. In another and Hepatology, 2020. study by Mohamed et al. [39], they documented a sig- [2] H. Islam, M. S. Metwally, A. F. Elalfy, A. Amr, S. S. Saleh, and niﬁcant correlation between MVD and pathological stage H. Mohamed, “Epidemiology and survival of colon cancer of the tumor and with vascular invasion which has an among Egyptians: a retrospective study,” Journal of Colo- inﬂuence on tumor depth of invasion. Consequently, the proctology, vol. 38, no. 1, pp. 24–29, 2018. depth of invasion has its impact on CRM as discussed [3] I. Marmol, C. Sanchez-de-Diego, A. Pradilla Dieste, earlier. E. Cerrada, and M. J. 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Publisher: Hindawi Publishing Corporation
Copyright: Copyright © 2020 M. Ashraf Balbaa et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ISSN: 2090-1402
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DOI: 10.1155/2020/6789709
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Abstract

Hindawi International Journal of Surgical Oncology Volume 2020, Article ID 6789709, 8 pages https://doi.org/10.1155/2020/6789709 Research Article Predictive Factors of Positive Circumferential and Longitudinal Margins in Early T3 Colorectal Cancer Resection 1 2 3 M. Ashraf Balbaa , Noha Elkady , and Emad M. Abdelrahman General Surgery Department, Faculty of Medicine, Menouﬁa University, Menouﬁa 32511, Egypt Pathology Department, Faculty of Medicine, Menouﬁa University, Menouﬁa 32511, Egypt General Surgery Department, Faculty of Medicine, Benha University, Benha 13511, Egypt Correspondence should be addressed to M. Ashraf Balbaa; ashraf_balbaa@hotmail.com Received 8 February 2020; Accepted 3 June 2020; Published 27 June 2020 Academic Editor: C. H. Yip Copyright © 2020 M. Ashraf Balbaa et al. )is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. Malignant involvement of circumferential resection margin (CRM) and longitudinal resection margin (LRM) after surgical resection of colorectal cancer (CRC) are associated with higher rates of recurrence and development of distant metastasis. )is can inﬂuence the overall patient’s prognosis. )e aim of the current study was to identify pathological factors as predictors for the involvement of resection margins in early T3 CRC. Patients and Methods. Fifty patients radiologically diagnosed to have cT3a/ b (CRC) were included in the study. After resection, the pathological examination was performed to identify patients with positive CRM and/or LRM. Relations between the diﬀerent pathological parameters and the CMR and LRM involvements were assessed. Results. Positive CRM was present in 17 cases (34%), while positive LRM was found in 6 cases (12%). )e involvement of both margins was signiﬁcantly associated with rectal tumors and tumors with inﬁltrative gross appearance, grade III, deeper invasion, and positive lymph node metastases. Also, there was a signiﬁcant association between both margins’ positivity and other pathological parameters as signet ring carcinoma, tumor budding, perineural and vascular invasion, high microvessel density (MVD), and sinusoidal vascular pattern, while the presence of necrosis and inﬁltrative advancing tumor front was signiﬁcantly associated with CRM involvement only. )e depth of tumor invasion and signet ring carcinoma were identiﬁed as independent predictor factors for positive CRM and LRM, respectively. Conclusion. Preoperative identiﬁcation of these pathological pa- rameters can be a guide to tailor the management plan accordingly. resection margin (CRM) as well as longitudinal resection 1. Introduction margin (LRM) can be considered the hallmark of a suc- Globally, Colorectal Cancer (CRC) is the third most com- cessful oncologic resection [5]. Many studies have dem- monly diagnosed cancer and the second cancer-related onstrated that CRM involvement is able to predict local th leading cause of death [1]. In Egypt, it occupies the 7 recurrence and poor prognosis among patients with rectal as among all cancers, where it represents 3.47% and 3% of well as colon cancer [5–7]. On the other hand, the LRM cancers in males and females, respectively [2]. Currently, the positivity has been shown to be a predictor for local re- treatment strategy for CRC patients involves a multimodal currence, development of distant metastasis, and decreased approach based on tumor-related characteristics and pa- disease-free survival [8–10]. In spite of conﬁning to standard tient-related factors [3]. However, surgery remains the surgical rules to achieve grossly negative resection margin mainstay curative treatment for patients with nonmetastatic (R0), still, positive resection margins are detected micro- CRC and the quality of surgical procedure can signiﬁcantly scopically on postoperative histopathological examination inﬂuence both short- and long-term disease outcomes [4]. [5, 11, 12]. )is can be clearly demonstrated in early T3 One of the crucial pillars of surgical quality is achieving tumors where surgery is the main line of therapy. For colon negative resection margins. Negative circumferential cancer, guidelines recommend neoadjuvant therapy to be 2 International Journal of Surgical Oncology ensure grossly free CRM of the rectum by sharp and precise used only in selected cases of T4 and not for T3 tumors [13, 14]. For rectal cancer, although NCCN guidelines [15] dissection at the anatomical fascial planes. Great care has been taken to avoid injury of the hypogastric nerve. recommend neoadjuvant therapy for T3 tumors, still ESMO guidelines [16] recommend neoadjuvant therapy for Labeling and orientation of the specimens were per- tumors> cT3b as a routine therapy and for cT3a/b tumors in formed before sending to the Pathology Department at the conditioned indications [17]. We assume that pathological Faculty of Medicine, Menouﬁa University. Surgical speci- features indicating rapidly dividing, inﬁltrative, and ag- mens were grossly examined to assess tumor site, size, and gressive tumors have an association with positive margins. gross appearance. Hematoxylin and Eosin (H&E) stained )e aim of this study was to explore the pathological factors slides were histologically examined using light microscopy as predictors for the involvement of resection margins of to conﬁrm the diagnosis. Identiﬁcation of diﬀerent tumor early T3 CRC. If these factors can be recognized preoper- pathological ﬁndings was performed, including histopath- ological type, grade, depth of invasion, and lymph node atively, intraoperative modulation of surgical techniques and/or the addition of other therapeutic modalities can be involvement. Special tumor characters had been evaluated as the presence of tumor-associated inﬂammation, desmo- applied. plasia, budding, necrosis, mitotic and apoptotic indices, perineural and vascular invasion, microvessel density 2. Patients and Methods (MVD), vascular pattern, and the pattern of advancing )is study included 50 radiologically selected patients to be tumor front. Special attention was paid to determine CRM cT3a/b tumors out of 196 cases of operable CRC that were and LRM involvement. )e circumferential margin was not candidates for neoadjuvant therapy. )e patients have deﬁned as the shortest distance measured from the mi- been operated upon at Surgery Departments of the Main croscopically deepest area of tumor inﬁltration to the stained Hospitals of Menouﬁa and Benha Universities, during the CRM. Positive CRM involvement was deﬁned as tumor presence in a distance ≤1 mm from the nonperitonealized period from January 2016 to May 2019. An approval to conduct the research was obtained from both institutes’ surface of resection or by serosal penetration of the peri- tonealized portions of the colon [18]. )e LRM was deﬁned ethical and research committees (No# 12/2015 SURG 7 and 0134-12/15). A written informed consent was obtained from as the distance from the tumor edge to the closest resection all included patients. Exclusion criteria included patients margin(s). Resection margin of 2 cm was considered ade- with locally advanced tumors with evidence of local inﬁl- quate [18]. tration to other organs or surrounding tissue cT3 c/d or T4 According to the involvement CRM, patients were di- or those who have been operated upon in emergency sit- vided into two groups (CRM-positive and CRM-negative uations, as perforated or obstructed cases. Metastatic cases groups). )e same was performed according to LRM in- and operable ones after receiving neoadjuvant therapy were volvement (LRM-positive and LRM-negative groups). Re- excluded as well. Detailed history has been obtained from all lations between the diﬀerent pathological ﬁndings and the CMR and LRM involvements were assessed. patients. Systematic physical examination was performed followed by full preoperative investigations, including co- Statistical analysis was performed using SPSS-20 (Statistical Package for Social Sciences version 20). Uni- lonoscopy and biopsy as well as complete metastatic workup. All biopsies were histologically conﬁrmed to be CRC. MRI variate analysis was performed to identify signiﬁcant for rectal cancer was performed to select patients with cT3a/ predictors of a positive CRM and positive LRM. Qualitative b. Spiral CT for colon cancer was performed to select T3 parameters were expressed as the frequency with per- tumors that extend to the pericolic tissue but not to adjacent centage rates and the Chi-square test was used to assess the organs. It was demonstrated as thickening and inﬁltration of statistically signiﬁcant association. On the other hand, pericolic fat. Surgical resection was performed to all cases quantitative parameters were expressed as a range (mini- mum and maximum), mean, and standard deviation where after thorough intraoperative assessment of the non- metastatic stage of the tumors. Surgical resection included Student’s t-test and Mann–Whitney U test were used to assess the statistical signiﬁcance. )e crude odds ratios right hemicolectomy, left hemicolectomy, sigmoidectomy, anterior resection, and abdominoperineal resection. Colonic (OR) and their 95 percent conﬁdence intervals (95% CI) were calculated for each variable. Pathological parameters resection was performed with at least 5 cm longitudinal resection margins with excision of the adjoining mesentery associated with positive CRM and those with positive LRM that harbors all the tumor-draining lymph nodes. Proximal with a P value<0.05 were included in a multivariate logistic ligation of the arterial supply of the resected portion was regression to identify those variables that are indepen- performed to ensure harvesting all the draining lymph nodes dently associated with either positive CRM or positive with subsequent removal of adjoining devascularized bowel LRM, respectively. by this ligation. Circumferential resection included resection of the retroperitoneal adventitial tissue of the cecum, as- 3. Results cending, or descending colon. For the rectal resection, at least 2 cm of grossly free distal margin was obtained. Due to )e mean age of the included patients was 63.8 ± 4.1 years the proximal high ligation of the inferior mesenteric artery, with more incidence in males (31 cases; 62%) than females the proximal longitudinal margin was very abundant. )e (19 cases; 38%). Forty-one (82%) cases were diagnosed as principles of total mesorectal excision were followed to colon cancer while 9 (18%) cases were rectal cancer. International Journal of Surgical Oncology 3 Table 1: Distribution of the studied cases according to diﬀerent Twenty-three cases were grossly fungating type (46%). clinicopathological parameters (n � 50). Adenocarcinoma represented almost half of the cases (26 cases; 52%) and the others were either mucinous (15 cases; No. (%) 30%) or signet ring carcinoma (9 cases; 18%). Positive CRM Sex was present in 17 cases (34%), while positive LRM was found Male 31 (62%) in 6 cases (12%) (Table 1). Female 19 (38%) )e study showed that positive CRM was signiﬁcantly Age (years) associated with rectal location (P � 0.004), inﬁltrative gross Median (min.–max.) 63 (49–72) pattern (P � 0.005), signet ring carcinoma (P � 0.002), Mean± SD 63.8± 4.1 Site deeper tumor invasion (P< 0.001) (Figure 1), grade III Colon 41 (82%) tumors (P � 0.034), invasive pattern of advancing tumor Rectum 9 (18%) front (P � 0.002) (Figure 2), positive lymph node metastasis Size (P � 0.001), tumor budding (P � 0.016), presence of ne- Median (min.–max.) 4 (3–6) crosis (P � 0.029), perineural and vascular invasion Mean± SD 4.3± 1 (P � 0.04 and 0.021), high MVD (P< 0.001), and presence of Gross appearance sinusoidal vascular pattern (P � 0.001) (Table 2). Ulcer 15 (30%) On the other hand, the study showed a signiﬁcant as- Inﬁltrating 12 (24%) sociation between positive LRM and rectal location Fungating 23 (46%) (P � 0.007), inﬁltrative gross pattern (P � 0.049), signet ring Histopathological type carcinoma (P< 0.001) (Figure 3), deeper tumor invasion Adenocarcinoma 26 (52%) Mucinous 15 (30%) (P � 0.021), grade III tumors (P � 0.042), positive lymph Signet ring 9 (18%) nodes involvement (P � 0.01), tumor budding (P � 0.018), Depth perineural and vascular invasion (P � 0.009 and 0.011), high Pericolorectal tissue/serosa 20 (40%) MVD (0.004), and sinusoidal vascular pattern (P � 0.001) Muscularis propria 30 (60%) (Figure 4) (Table 2). Advancing tumor front Table 3 shows the univariate analysis of the diﬀerent Invasive pattern 37 (74%) pathological parameters and their relations with both pos- Broad pushing margin (cohesive pattern) 13 (26%) itive CRM and LRM. Multivariate logistic regression Desmoplasia 20 (40%) revealed that invasion of pericolorectal tissue/serosa was the Tumor budding 18 (36%) independent predictor factor for positive CMR (P< 0.001), Lymph nodes involvement 16 (32%) Inﬂammation 27 (54%) with the marginal signiﬁcance of inﬁltrative gross pattern Necrosis 19 (38%) (P � 0.055), while signet ring type was the independent Perineural invasion 5 (10%) predictor factor for positive LRM (P � 0.035) with the Vascular invasion 10 (20%) marginal signiﬁcance of high MVD (P � 0.53) and sinu- Tumor grade soidal vascular pattern (P � 0.54) (Table 4). G1 15 (30%) GII 17 (34%) 4. Discussion GIII 18 (36%) Mitotic index Presence of gross or microscopic evidence of malignant Median (min.–max.) 8 (1–11) tumor at the resection margins of CRC specimen is a Mean± SD 6.4± 3.1 Apoptotic index universally poor prognostic factor [19]. Previous studies Median (min.–max.) 9 (2–15) have concentrated on the CRM of the rectum as a very strong Mean± SD 7.7± 3.7 predictor of tumor recurrence. In a meta-analysis that in- MVD cluded over 17,000 patients, Nagtegaal and Quirke [20] were Median (min.–max.) 8 (2–18) able to demonstrate that involvement of CRM was a strong Mean± SD 7.7± 3.4 predictor of local recurrence (HR 2.7, 95% CI 1.7–4.3), Sinusoidal vascular pattern distant metastases (HR 2.8, 95% CI 1.9–4.3), and survival as Negative 39 (78%) well (HR 1.7, 95% CI 1.3–2.3). On the other hand, for the Positive 11 (22%) colon, LRM had great attention in research neglecting the Positive longitudinal resection margin 6 (12%) signiﬁcance of its radial margin. As demonstrated by Amri Positive circumferential resection margin 17 (34%) et al. [5], a cohort of nearly 1000 patients was essential to have enough statistical power to show the consequences of positive CRM of colon cancer. Believing in the signiﬁcance cancer [21] and resection of the retroperitoneal adventitial of both margins, CRM and LRM as predictors of the pa- soft tissue of the partially peritonealized colon [5]. Bujko tient’s outcome, the current study has explored diﬀerent et al. [22] demonstrated in their review that subclinical distal pathological factors that inﬂuence the positivity of both bowel intramural spread is present within 1 cm distally from resection margins in both colon and rectum. visible tumor edge in a considerable proportion of patients. )e key for the optimal CRM is the respect to the Consequently, for patients who are undergoing anterior embryonic fascia by total mesorectal excision for rectal resection for low-lying cancer, a distal bowel clear margin of 4 International Journal of Surgical Oncology compared with the previously reported prevalence in similar studies. Positive rates of CRM were reported to be 5.3% by Armi et al. [5], 17.6% by Kang et al. [26], 22% by Eriksen et al., and 28% by Birbeck et al. [27], while rates of positive LRM were reported to be 1.5% by Zeng et al. [10], 6.83% by Orosco et al. [28], and 7.9% by Kanters et al. [25]. In the current study, multivariate analysis has demon- strated that deeper tumor invasion up to the pericolorectal tissue/serosa was an independent predictor of positive CRM. )is observation is matching with Rickles et al. [11] and Warrier et al. [12] who demonstrated the signiﬁcant relation Figure 1: Positive circumferential margin in the case of mucoid between tumor “T” depth of invasion and positive CRM. )e carcinoma with signet ring diﬀerentiation (H&E 200). inﬁltrative gross pattern of tumors has been shown to have marginal signiﬁcance as an independent predictor as well. Although the results did not reach the statistical threshold of signiﬁcance, it seems that both parameters are coincident, as inﬁltrating tumor pattern is directly related to the depth of tumor invasion. In the previous studies [29, 30], it has been established that mucinous and signet ring types of CRC have a worse prognosis compared to other varieties of CRC. )ey are characterized by being prevalent in more advanced stages of the disease, with a much higher rate of lymphatic metastasis, serous inﬁltration, and peritoneal dissemination. In addi- tion, these two types of carcinomas have higher rates of the local extension, which leads to a lesser chance for curative resection and decreases the overall survival rate [31]. Signet Figure 2: Advancing tumor front (invasive type) in the case of ring carcinomas are considered high-grade adenocarci- high-grade adenocarcinoma (H&E 200). nomas. In these tumors, there is a loss of E-cadherin, cell adherence, tight junctions, and cell-cell interaction with the at least >1 cm is minimally acceptable. On the other hand, acquisition of stem cell-like characteristics leading to en- Hohenberger et al. [23] concluded in their study that the hanced tumor growth, invasion, and metastasis [32, 33]. standard LRM in colon cancer should be at least 5 cm on Obviously, the mucin provides pressure on the bowel wall with more tendency for tumor extension. On the other hand, both sides of the tumor. Conﬁning to these standards was performed during surgical resection in the current study. the intracellular mucin display may induce swelling of the tumor cells, due to its ability to imbibe water, and allow them Aggressive tumors are associated with uncontrolled cell proliferation and extensive invasion and metastasis. Un- to pass through the bowel layers with further dissemination [34]. )is coincides with our observations as it has been controlled proliferation is due to the activation of cell cycle genes and the loss of apoptosis-inducing ones and is re- shown that signet ring carcinoma was an independent ﬂected histologically as high mitotic and low apoptotic in- predictor for positive LRM in colorectal cancer. In a study by dices. While the ability for invasion is due to oncological Rickles et al. [11], they have demonstrated that signet ring metaplasticity and epithelial-mesenchymal transition where cell carcinoma and mucinous adenocarcinoma are inde- the cells lose adhesion and acquire cytoskeleton reorgani- pendent factors for CRM involvement. zation, contractility, and invadopodia and then become Neovascularization is an important factor in cancer growth and metastasis because it is involved in the capable of stromal invasion. )e advancing tumor front is one of the determinants of tumor invasion and in aggressive transport of various nutrients to the tumor cells [35]. Vascular changes in tumor areas are due to mediators tumors; it is usually an invasive pattern [24]. Positivity of the resection margins has been shown to be secreted by tumor cells or the surrounding microenvi- ronment. )e vascular patterns are either capillary-like or inﬂuenced by a lot of factors as tumor location, stage, grade, lymph node metastases, positive vascular and perineural sinusoid-like vessels which form a cobweb-like network invasion, and pattern of advancing tumor front and facilitate tumor invasion and metastasis [36]. [5, 11, 12, 25]. )e previously mentioned factors have been Microvessel density (MVD) has been documented to have demonstrated in the current study, in addition to other a prognostic value in colon cancer [37]. In the current pathological parameters that were signiﬁcantly associated study, MVD has been shown to have a marginal signiﬁ- with positive margins, such as signet ring carcinoma, tumor cance to be an independent predictor for positivity of the of LRM. )e limited number of included cases could be a budding, necrosis, high MVD, and ectatic vascular pattern. )e selection of higher “T” of the included cases within the factor that inﬂuenced the results and the statistical power threshold of signiﬁcance could have been reached if the present study may explain the encountered slightly higher rates of positive CRM (34%) and LRM (12%) when number of patients was quite larger. In the literature, we International Journal of Surgical Oncology 5 Table 2: Relation between circumferential and longitudinal resection margins and diﬀerent clinicopathological parameters (n � 50). Circumferential resection Longitudinal resection margin margin Test of sig. P Test of sig. P Negative Positive Negative Positive (n � 33) (n � 17) (n � 44) (n � 6) Sex Male 20 (60.6%) 11 (64.7%) 27 (61.4%) 4 (66.7%) 2 2 χ � 0.080 0.777 χ � 0.063 1.000 Female 13 (39.4%) 6 (35.3%) 17 (38.6%) 2 (33.3%) Age (years) 63.5 Median (Min.–max.) 63 (49–72) 66 (55–70) 63 (49–72) t � 0.507 0.615 (55–67) t � 0.792 0.432 Mean± SD. 63.5± 4.2 64.2± 4 63.9± 4.1 62.5± 4.5 Tumor site Colon 31 (93.9%) 10 (58.8%) 39 (88.6%) 2 (33.3%) 2 ∗ ∗ 2 ∗ ∗ χ � 9.374 0.004 χ �10.941 0.007 Rectum 2 (6.1%) 7 (41.2%) 5 (11.4%) 4 (66.7%) Tumor size Median (min.–max.) 4 (3–6) 4 (3–6) 4 (3–6) 4.5 (3–6) t � 0.376 0.709 t � 0.886 0.380 Mean± SD. 4.3± 1 4.4± 0.9 4.3± 0.9 4.7± 1.2 Gross appearance Ulcer 9 (27.3%) 6 (35.3%) 14 (31.8%) 1 (16.7%) 2 2 ∗ ∗ ∗ ∗ Inﬁltrating 4 (12.1%) 8 (47.1%) χ �10.448 0.005 8 (18.2%) 4 (66.7%) χ � 5.470 0.049 Fun gating 20 (60.6%) 3 (17.6%) 22 (50%) 1 (16.7%) Histopathological type Adenocarcinoma 23 (69.7%) 3 (17.6%) 25 (56.8%) 1 (16.7%) 2 2 ∗ ∗ ∗ ∗ Mucinous 7 (21.2%) 8 (47.1%) χ �12.624 0.002 15 (34.1%) 0 (0%) χ �13.543 <0.001 Signet ring 3 (9.1%) 6 (35.3%) 4 (9.1%) 5 (83.3%) Depth Pericolorectal tissue/serosa 3 (9.1%) 17 (100%) 15 (34%) 5 (83.3%) ∗ ∗ ∗ FE <0.001 χ � 5.35 0.021 Muscularis propria 30 (90.9%) 0 (0%) 29 (66%) 1 (16.7%) Tumor grade I 13 (39.4%) 2 (11.8%) 15 (34.1%) 0 (0%) 2 ∗ ∗ 2 ∗ ∗ II 12 (36.4%) 5 (29.4%) χ � 6.742 0.034 16 (36.4%) 1 (16.7%) χ � 5.685 0.042 III 8 (24.2%) 10 (58.8%) 13 (29.5%) 5 (83.3%) Advancing tumor front Invasive pattern 20 (60.6%) 17 (100%) 31 (70.5%) 6 (100%) 2 2 ∗ ∗ Broad pushing margin χ � 9.050 0.002 χ � 2.396 0.122 13 (39.4%) 0 (0%) 13 (29.5%) 0 (0%) (cohesive pattern) 2 2 ∗ ∗ ∗ ∗ Lymph nodes involvement 5 (15.2%) 11 (64.7%) χ �12.662 0.001 11 (25%) 5 (83.3%) χ � 8.257 0.010 2 2 Inﬂammation 15 (45.5%) 12 (70.6%) χ � 2.853 0.091 23 (52.3%) 4 (66.7%) χ � 0.440 0.674 2 2 Desmoplasia 11 (33.3%) 9 (52.9%) χ �1.797 0.180 16 (36.4%) 4 (66.7%) χ � 2.020 0.202 2 ∗ 2 ∗ ∗ Tumor budding 8 (24.2%) 10 (58.8%) χ � 5.824 0.016 13 (29.5%) 5 (83.3%) χ � 6.630 0.018 2 2 ∗ ∗ Necrosis 9 (27.3%) 10 (58.8%) χ � 4.741 0.029 15 (34.1%) 4 (66.7%) χ � 2.378 0.184 2 ∗ ∗ 2 ∗ ∗ Perineural invasion 1 (3%) 4 (23.5%) χ � 5.239 0.040 2 (4.5%) 3 (50%) χ �12.121 0.009 2 2 ∗ ∗ ∗ ∗ Vascular invasion 3 (9.1%) 7 (41.2%) χ � 7.219 0.021 6 (13.6%) 4 (66.7%) χ � 9.280 0.011 Mitotic index Median (min.–max.) 7 (1–11) 8 (2–10) 7 (1–11) 7.5 (4–10) U � 265.50 0.620 U � 97.50 0.311 Mean± SD 6± 3.2 6.4± 2.9 5.9± 3.1 7.5± 2.3 Apoptotic index Median (min.–max.) 7 (2–13) 10 (2–15) 9 (2–15) 7.5 (3–11) U � 207.50 0.132 U � 124.0 39.0 Mean± SD 7.2± 3.5 8.7± 4.1 7.8± 3.7 7.2± 3.9 MVD Median (min.–max.) 7 (2–13) 11 (7–18) 7 (2–18) 11 (10–11) ∗ ∗ ∗ ∗ U � 88.0 <0.001 U � 39.0 0.004 Mean± SD 6.3± 3 10.2± 2.5 7.3± 3.4 10.7± 0.5 Sinusoidal vascular pattern Negative 29 (87.9%) 10 (58.8%) 38 (86.4%) 1 (16.7%) 2 2 ∗ ∗ ∗ ∗ χ � 5.520 0.001 χ �14.947 0.001 Positive 4 (12.1%) 7 (41.2%) 6 (13.6%) 5 (83.3%) χ : Chi-square test; t: Student’s t-test; U: Mann–Whitney test; FE: Fisher’s Exact test; P: P value for association between negative and positive; : statistically signiﬁcant at P< 0.05. 6 International Journal of Surgical Oncology Figure 3: Signet ring carcinoma associated with positive longitudinal margin and creeping malignant cells beneath the intestinal glands (H&E 200). Figure 4: High-grade invasive adenocarcinoma associated with sinusoidal vascular pattern (H&E 200). Table 3: Univariate analysis for the clinicopathological parameters aﬀecting longitudinal and circumferential margins (n � 50). Longitudinal resection margin Circumferential resection margin P OR (95% CI) P OR (95% CI) Sex (male) 0.802 1.259 (0.208–7.638) 0.777 1.192 (0.353–4.018) Age (years) 0.427 0.924 (0.761–1.123) 0.607 1.039 (0.897–1.204) ∗ ∗ ∗ ∗ Tumor site (rectum) 0.005 15.60 (2.251–108.12) 0.007 10.850 (1.932–60.930) Tumor size 0.376 1.513 (0.605–3.781) 0.702 1.128 (0.609–2.088) ∗ ∗ ∗ ∗ Gross appearance (inﬁltrating) 0.021 9.0 (1.398–57.944) 0.010 6.444 (1.567–26.506) ∗ ∗ ∗ ∗ Histopathological type (signet ring) 0.001 50.0 (4.626–540.444) 0.032 5.455 (1.159–25.662) ∗ ∗ Tumor grade (Grade III) 0.030 11.923 (1.266–112.287) 0.019 4.464 (1.277–15.608) ∗ ∗ ∗ Depth (pericolorectal tissue/Serosa) 0.030 11.923 (1.266–112.29) <0.001 75.0 (11.291–498.196) Advancing tumor front 0.098 0.152 (0.016–1.411) 0.998 — Desmoplasia 0.174 3.50 (0.576–21.282) 0.184 2.250 (0.680–7.442) ∗ ∗ ∗ ∗ Tumor budding 0.030 11.923 (1.266–112.29) 0.019 4.464 (1.277–15.608) ∗ ∗ ∗ ∗ Lymph nodes involvement 0.018 15.0 (1.576–142.724) 0.001 10.267 (2.592–40.669) Inﬂammation 0.511 1.826 (0.303–11.020) 0.097 2.880 (0.827–10.034) ∗ ∗ Necrosis 0.143 3.867 (0.634–23.585) 0.033 3.810 (1.110–13.070) ∗ ∗ ∗ ∗ Vascular invasion (positive) 0.009 12.667 (1.888–84.965) 0.013 7.0 (1.515–32.333) Mitotic index 0.251 1.220 (0.869–1.713) 0.626 1.050 (0.863–1.277) Apoptotic index 0.705 0.956 (0.759–1.205) 0.171 1.125 (0.950–1.333) ∗ ∗ MVD (high) 0.042 1.401 (1.012–1.940) 0.001 1.731 (1.234–2.429) ∗ ∗ ∗ ∗ Sinusoidal vascular pattern 0.003 31.667 (3.133–320.06) 0.025 5.075 (1.223–21.065) OR: Odd`s ratio; CI: conﬁdence interval; #: all variables with P< 0.05 were included in the multivariate; : statistically signiﬁcant at P≤ 0.05. Table 4: Multivariate logistic regression (Forward: Wald) for circumferential and longitudinal resection margins. B SE Sig. OR Gross appearance (inﬁltrating) 2.371 1.285 0.055 10.713 Circumferential resection margin Depth (pericolorectal tissue/serosa) 4.590 1.172 <0.001 98.460 MVD (high) 0.679 0.351 0.053 1.972 Longitudinal resection margin Vascular pattern (sinusoidal) 3.780 1.961 0.054 43.820 Histopathological type (signet ring) 4.684 2.216 0.035 108.229 B: unstandardized coeﬃcients; OR: odds ratio; CI: conﬁdence interval; LL: lower limit. International Journal of Surgical Oncology 7 could not trace a similar model correlating the neo- References vascularization with positive involvement of CRC resec- [1] M. C. Wong, J. Huang, V. Lok et al., “Diﬀerences in incidence tion margins. However, in a study by Tarta et al. 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Predictive Factors of Positive Circumferential and Longitudinal Margins in Early T3 Colorectal Cancer Resection

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