Predictors for lymph node metastasis in T1 colorectal cancer

• Introduction
• Patients and methods
• Statistical analyses
• Results
• Patient characteristics
• Relationship between LNM and histopathologic factors in surgically resected T1 CRC
• Incidence of LNM in surgically resected subgroup by classic criteria
• Follow-up results in endoscopically resected T1 CRC
• Discussion
• References

Background and study aims: It is critical that the risk of lymph node metastasis (LNM) is evaluated for determining the suitability of endoscopic resection for T1 colorectal cancer (CRC). Reported risk factors for LNM in completely resected T1 CRC are deep submucosal invasion, grade 3, angiolymphatic invasion, and budding. The aim of the present study was to identify the histopathologic factors associated with LNM in T1 CRC

Patients and methods: The study involved 435 patients with T1 CRC treated by endoscopic or surgical resection between January 2001 and April 2010 at the National Cancer Center, Korea. The 435 patients were classified into two groups – those undergoing surgical resection (n = 324) and those undergoing endoscopic resection (n = 111). In the surgically resected group, details regarding depth of submucosal invasion, angiolymphatic invasion, tumor grade, budding, and background adenoma (BGA) were evaluated with respect to presence or absence of LNM. In the endoscopically resected group, the results of follow-ups and additional salvage surgeries were studied.

Results: In the surgically resected group, LNM was detected in 42 patients (13.0 %). Grade 3, angiolymphatic invasion, budding, and the absence of BGA were identified as factors associated with LNM in univariate and multivariate analyses (P < 0.05). Among the 50 patients in the endoscopically resected group with high risk, three were diagnosed as being LNM-positive during the follow-up period. There was no LNM in the endoscopically resected group with low risk.

Conclusions: Grade 3, angiolymphatic invasion, budding, and the absence of BGA are the risk factors that predict LNM in patients with T1 CRC. In cases where endoscopically resected T1 CRC has no risk factor, cautious follow-up could be recommended. However, if the tumor has any risk factor, additional surgical resection should be considered.

Introduction

Endoscopic resection of Tis (carcinoma in situ: intraepithelial or invasion of lamina propria) colorectal cancer (CRC) is accepted as a curative therapy because this lesion carries no risk of lymph node metastasis (LNM) [1] [2]. However, because LNM occurs in 7 % – 15 % of T1 (tumor invades submucosa) CRC cases, endoscopic resection for T1 CRC should be used selectively [3] [4] [5] [6].

Many previous researchers have shown that deep submucosal invasion, angiolymphatic invasion, and grade 3 are associated with LNM in T1 CRC. Budding, also known as “sprouting” is one of the histological patterns of cancer growth at the margin, defined as isolated cancer cells in the otherwise normal tissue. Some researchers have demonstrated that budding is significantly associated with LNM in CRC [5] [7].

Background adenoma (BGA), also known as pre-existing adenoma, is defined as benign adenomatous tissue contiguous to resected carcinomas. Thus, in relation to the adenoma – carcinoma sequence, a BGA may be the original adenoma from which the carcinoma originated [8]. Some CRCs, however, are not accompanied by BGA [9] [10]. The absence of BGA in the tumor has been considered a histologic criteria of de novo cancers [11]. We reported previously that the absence of BGA is related to non-lifting sign in patients with T1 CRC [12]. Little is known, however, about the pathogenesis or clinicopathologic characteristics of CRCs without BGA.

The present study sought to identify the histopathologic factors associated with LNM in T1 CRC.

Patients and methods

Between January 2001 and April 2010, a total of 543 patients with T1 CRC underwent endoscopic or surgical resection at the National Cancer Center, Korea. Patients who were diagnosed with familial adenomatous polyposis (n = 16), those who underwent surgery after preoperative chemoradiation therapy (n = 41), and those who underwent surgery because of synchronous advanced CRC (n = 51) were excluded. Thus, 435 patients were included in the study ([Fig. 1]).

Clinical data from the CRC database and clinical charts were reviewed retrospectively. According to the Paris classification, endoscopic type was classified into four types: pedunculated (0-Ip), sessile (0-Is), flat (0-IIa), and depressed (0-IIc) [13]. All of the lesions were submitted in their entirety, and pathological diagnoses were performed by a pathologist (H.J.C.).

The submucosal invasion depth was evaluated using Kudo’s classification, as sm1 (infiltration into the upper third of the submucosal layer), sm2 (middle third), or sm3 (lower third) in surgically resected specimens [14]. For endoscopically resected sessile or flat tumors, the cut-off limit between sm1 and sm2 was 1000 μm of submucosal layer according to the Paris classification, and a submucosal invasion exceeding 2000 μm was defined as sm3. For endoscopically resected pedunculated tumors, the cut-off limit between sm1 and sm2 was the level of the neck, and a submucosal invasion exceeding 3000 mm from the neck was defined as sm3. The method proposed by Kitajima et al. was used for the measurement of submucosal depth [15].

Angiolymphatic invasion was defined as the presence of cancer cells within endothelial-lined channels.

Grading of the tumor was determined according to World Health Organization criteria. Grade 1 (well differentiated adenocarcinoma) exhibits glandular structures in > 95 % of the tumor; grade 2 (moderately differentiated adenocarcinoma) has 50 % – 95 %; grade 3 (poorly differentiated adenocarcinoma) has < 50 % [16].

An isolated cell or a small cluster of < 5 carcinoma cells in the invasive front was defined as a budding focus, with positive tumor budding defined as > 10 budding foci viewed at × 200 magnification [17]. BGA was defined as an adenomatous component microscopically contiguous to resected T1 CRC ([Fig. 2] and [Fig. 3]).

The 435 included patients were classified into two groups – those patients who underwent surgical resection and those who underwent endoscopic resection. Of 435 included patients, 149 patients underwent primary surgical resection and 286 patients underwent primary endoscopic resection. Of the 286 patients who underwent primary endoscopic resection, 175 patients underwent additional surgical resection, based on the presence of risk factors: positive or undetermined resection margins, deep submucosal invasion (sm2 or sm3), angiolymphatic invasion, grade 3, and budding. Thus, a total of 324 patients (149 with primary surgery + 175 with additional surgery) were included in the surgically resected group ([Fig. 1]). Of the 286 patients who underwent primary endoscopic resection, 111 patients underwent no additional surgery. These 111 patients were included in the endoscopically resected group, and classified into two subgroups – a low risk group (without risk factors) and a high risk group (with risk factors) ([Fig. 1]). The endoscopically resected group was excluded in the statistical analysis of LNM. The patients in the endoscopically resected group were assessed immediately afterwards by computed tomography (CT) scanning of the abdomen and chest and by measurements of serum carcinoembryonic antigen (CEA) concentrations. Follow-ups included colonoscopy 6 months later, and annual CT scan, serum CEA measurement, and colonoscopy. The mean follow-up period was 36 months (range 12 – 60 months). The LNM status was evaluated on the basis of radiologic criteria. The criteria for an LNM to be positive on CT scanning were: (1) a single regional node larger than 1 cm, or a cluster of three or more regional nodes each less than 1 cm in diameter (in patient with colon cancer); (2) nodes greater than 3 mm in the perirectal area, or nodes larger than 1 cm in diameter in the pelvis (in patient with rectal cancer) [18] [19].

In the surgically resected group, details regarding the depth of submucosal invasion, angiolymphatic invasion, tumor grade, budding, and BGA were evaluated with regard to the presence or absence of LNM. In the endoscopically resected group, the results of follow-ups and additional salvage surgeries were studied.

The study was approved by the Institutional Review Board of the National Cancer Center, Korea (NCCNCS-10 – 416).

Statistical analyses

The chi-squared test and Fisher’s exact test were used to estimate relationships between histopathologic factors and LNM. Multivariate logistic regression analyses were used to identify the risk factors associated with LNM. Statistical significance was established at P < 0.05.

Results

Patient characteristics

The 435 included patients consisted of 287 men and 148 women, with a mean age of 60.6 years (range 26 – 89 years). Of these, 324 underwent surgical resection and 111 underwent endoscopic resection. The mean tumor size was 18.9 ± 12.5 mm (range 5 – 115 mm). There were 32 cases of pedunculated tumors, 313 sessile, 41 flat, and 49 depressed-type tumors ([Table 1]).

Relationship between LNM and histopathologic factors in surgically resected T1 CRC

In the 324 surgically resected patients, 42 (13.0 %) were diagnosed as being LNM-positive. Grade 3 (P < 0.001) and angiolymphatic invasion (P < 0.001) were independent factors associated with LNM in patients with T1 CRC ([Table 2] and [Table 3]).

Budding was also statistically significant in both univariate analysis (P = 0.002) and in multivariate logistic regression analysis (P = 0.037) ([Table 2] and [Table 3]).

The absence of BGA was significantly related to a high incidence of LNM (P = 0.047) ([Table 2]). Multivariate logistic regression analysis also showed that the absence of BGA (P = 0.013) was an independent factor associated with LNM in patients with T1 CRC ([Table 3]).

Incidence of LNM in surgically resected subgroup by classic criteria

The classic criteria were based on three risk factors, submucosal invasion depth, tumor grade, and angiolymphatic invasion. [Table 4] shows the incidence of LNM in each subgroup of surgically resected patients with respect to the classic criteria. In 53 patients in the low risk group, two patients were diagnosed as being LNM-positive, and both of them had a histopathologic feature of budding. In the high risk group with sm2 /3 only (n = 118), two patients were diagnosed as being LNM-positive, and both of them had two histopathologic features of budding and the absence of BGA ( [Table 4]).

Follow-up results in endoscopically resected T1 CRC

In the endoscopically resected group, a mean number of 3 (range 1 – 5) follow-up CT scans and 4 (range 2 – 6) follow-up endoscopies were done during a mean follow-up period of 36 months (range 12 – 60 months).

In the 61 patients in the low risk group, no evidence of recurrence or LNM was detected during the follow-up period. The 50 patients in the high risk group had co-morbidities or refused additional surgery. Local recurrence were detected on follow-up endoscopy in four patients in this group and one patient was found to be LNM-positive on follow-up CT scan. All of these five patients underwent additional salvage surgery, and three of them were diagnosed to be LNM-positive. In all of these three patients, the original T1 CRCs that were endoscopically resected had the risk factor of angiolymphatic invasion.

Discussion

Although endoscopic resection has been utilized recently to treat patients with T1 CRC, its indications are limited due to the risk of LNM. The reported risk factors for LNM in patients with completely resected T1 CRC include deep submucosal invasion, angiolymphatic invasion, grade 3, and budding [3] [4] [5] [6] [20] [21] [22].

The finding from the current study that angiolymphatic invasion and grade 3 are independent risk factors associated with LNM in patients with T1 CRC, was in good agreement with many earlier studies. Therefore, angiolymphatic invasion and grade 3 are probably the most relevant factors for predicting LNM in patients with T1 CRC.

According to the Paris classification, endoscopic resection can be considered safe when submucosal invasion depth is < 1000 μm [13]. A Japanese collaborative study reported that the rate of LNM was 0 % in both non-pedunculated T1 CRC if submucosal depth was < 1000 μm and in pedunculated T1 CRC with head and stalk invasion to a submucosal depth of < 3000 μm if lymphatic invasion was negative [15]. In the current study, however, submucosal depth was found to be not significantly related to LNM, which is in agreement with other studies showing a weak relationship between submucosal depth and LMN in patients with T1 CRC [5] [23] [24]. In contrast, many earlier studies showed that submucosal depth was a significant risk factor for LNM in patients with T1 CRC [6] [14] [25]. The relationship between submucosal depth and LNM requires further evaluation, indicating the need for more research in this area.

Another histopathologic factor related to LNM is tumor budding, defined as isolated cancer cells in the invasive front of the tumor. It has been shown previously that budding is a risk factor for LNM in pedunculated and subpedunculated T1 CRCs [5]. The results presented here expand on these earlier findings, showing that budding is related to LNM in patients with T1 CRC.

Most CRCs develop from adenomatous polyps through the adenoma – carcinoma sequence [26], although some of these tumors develop de novo [9] [10]. It has been estimated that de novo cancers account for approximately 22 % of early CRCs, with the absence of adenomatous remnants in the tumor being a histologic criterion of de novo cancers [11]. Although it is known that de novo colon cancers lack K-ras mutations [27] [28], the natural history and molecular genetic anomalies associated with de novo cancers remain largely unknown. Thus, it is not clear whether the absence of BGA in CRC is the result of the de novo pathway or rapid tumor growth. Although the exact pathogenic mechanism associated with the absence of BGA from CRCs has not been determined, these tumors may show more aggressive biologic behavior. We showed previously that the absence of BGA was related to the non-lifting sign in patients with T1 CRC [12]. In evaluating the relationships between histopathologic factors and LNM in T1 CRC, we found that the absence of BGA was significantly related to LNM. Moreover, to our knowledge, the current study is the first to show that the absence of BGA is a risk factor associated with LNM in T1 CRC patients.

This study was limited in that many of the T1 CRC cases without risk factors were excluded in the LNM analysis because they did not undergo surgery and this may have introduced statistical bias. In future studies, larger sample sizes and longer follow-up periods may reduce such statistical bias.

In conclusion, the findings presented here demonstrate the relationship between histopathologic factors and LNM in T1 CRC patients. Grade 3, angiolymphatic invasion, budding, and the absence of BGA are risk factors for LNM in T1 CRC. Thus, these may be useful factors for predicting LNM and determining the suitability of endoscopic resection in patients with T1 CRC.

We hereby propose a decision rule for clinical purposes based on the current results. In cases where endoscopically resected T1 CRC has no risk factor, cautious follow-up could be recommended. However, if the tumor has any risk factor, additional surgical resection should be considered together with the co-morbidities of the patient.

Competing interests: None

• References

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Corresponding author

• References

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• 4 Kikuchi R, Takano M, Takagi K et al. Management of early invasive colorectal cancer. Risk of recurrence and clinical guidelines. Dis Colon Rectum 1996; 38: 1286-1295
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• 5 Sohn DK, Chang HJ, Park JW et al. Histopathological risk factors for lymph node metastasis in submucosal invasive colorectal carcinoma of pedunculated or semipedunculated type. J Clin Pathol 2007; 60: 912-915
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  CrossrefPubMedSearch in Google Scholar
• 7 Shimomura T, Ishiguro S, Konishi H et al. New indication for endoscopic treatment of colorectal carcinoma with submucosal invasion. J Gastroenterol Hepatol 2004; 19: 48-55
  CrossrefPubMedSearch in Google Scholar
• 8 Jass JR. Do all colorectal carcinomas arise in preexisting adenomas?. World J Surg 1989; 13: 45-51
  CrossrefPubMedSearch in Google Scholar
• 9 Kuramoto S, Oohara T. Minute cancers arising de novo in the human large intestine. Cancer 1988; 61: 829-834
  CrossrefPubMedSearch in Google Scholar
• 10 Shimoda T, Ikegami M, Fujisaki J et al. Early colorectal carcinoma with special reference to its development de novo. Cancer 1989; 64: 1138-1146
  CrossrefPubMedSearch in Google Scholar
• 11 Goto H, Oda Y, Murakami Y et al. Proportion of de novo cancers among colorectal cancers in Japan. Gastroenterology 2006; 131: 40-46
  CrossrefPubMedSearch in Google Scholar
• 12 Han KS, Sohn DK, Choi DH et al. Prolongation of the period between biopsy and EMR can influence the nonlifting sign in endoscopically resectable colorectal cancer. Gastrointest Endosc 2008; 67: 97-102
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  CrossrefPubMedSearch in Google Scholar
• 14 Kudo S. Endoscopic mucosal resection of flat and depressed types of early colorectal cancer. Endoscopy 1993; 25: 455-461
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• 15 Kitajima K, Fujimori T, Fujii S et al. Correlations between lymph node metastasis and depth of submucosal invasion in submucosal invasive colorectal carcinoma: a Japanese collaborative study. J Gastroenterol 2004; 39: 534-543
  PubMedSearch in Google Scholar
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  Search in Google Scholar
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  CrossrefPubMedSearch in Google Scholar
• 18 Balthazar EJ, Megibow AJ, Hulnick D et al. Carcinoma of the colon: detection and preoperative staging by CT. AJR Am J Roentgenol 1988; 150: 301-306
  CrossrefPubMedSearch in Google Scholar
• 19 Rifkin MD, Ehrlich SM, Marks G. Staging of rectal carcinoma: prospective comparison of endorectal US and CT. Radiology 1989; 170: 319-322
  PubMedSearch in Google Scholar
• 20 Kawamura YJ, Sugamata Y, Yoshino K et al. Endoscopic resection for submucosally invasive colorectal cancer. Is it feasible?. Surg Endosc 1999; 13: 224-227
  CrossrefPubMedSearch in Google Scholar
• 21 Tanaka S, Haruma K, Teixeira CR et al. Endoscopic treatment of submucosal invasive colorectal carcinoma with special reference to risk factors for lymph node metastasis. J Gastroenterol 1995; 30: 710-717
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• 22 Sakuragi M, Togashi K, Konishi F et al. Predictive factors for lymph node metastasis in T1 stage colorectal carcinomas. Dis Colon Rectum 2003; 46: 1626-1632
  CrossrefPubMedSearch in Google Scholar
• 23 Choi DH, Sohn DK, Chang HJ et al. Indications for subsequent surgery after endoscopic resection of submucosally invasive colorectal carcinomas: a prospective cohort study. Dis Colon Rectum 2009; 52: 438-445
  CrossrefPubMedSearch in Google Scholar
• 24 Tateishi Y, Nakanishi Y, Taniguchi H et al. Pathological prognostic factors predicting lymph node metastasis in submucosal invasive (T1) colorectal carcinoma. Mod Pathol 2010; 23: 1068-1072
  CrossrefPubMedSearch in Google Scholar
• 25 Nascimbeni R, Burgart LJ, Nivatvongs S et al. Risk of lymph node metastasis in T1 carcinoma of the colon and rectum. Dis Colon Rectum 2002; 45: 200-206
  CrossrefPubMedSearch in Google Scholar
• 26 Vogelstein B, Fearon ER, Hamilton SR et al. Genetic alterations during colorectal-tumor development. N Engl J Med 1988; 319: 525-532
  CrossrefPubMedSearch in Google Scholar
• 27 Umetani N, Sasaki S, Masaki T et al. Involvement of APC and K-ras mutation in non-polypoid colorectal tumorigenesis. Br J Cancer 2000; 82: 9-15
  CrossrefPubMedSearch in Google Scholar
• 28 Yashiro M, Carethers JM, Laghi L et al. Genetic pathways in the evolution of morphologically distinct colorectal neoplasm. Cancer Res 2001; 61: 2676-2683
  PubMedSearch in Google Scholar