Contributing Factors on Lymph Node Yield after Surgery for Mid-Low Rectal Cancer

Metastatic lymph nodes are the most potent prognostic factor after curative resection of rectal cancer.1 Whether the tumor metastasizes to regional lymph nodes is the key consideration not only for the prognosis,2 but also for applying adjuvant therapy. For accurate nodal staging after surgery, the number of lymph nodes examined is clinically important.3, 4 In particular, in patients with no metastatic lymph nodes, the number of lymph nodes identified in surgical specimens is critical for an accurate diagnosis. Inadequate lymph node assessment may affect survival, since it could be associated with understaging the disease. For this reason, the College of American Pathologists recommends examining a minimum of 12 lymph nodes to accurately stage node-negative rectal cancer5 and the Tumor-Node-Metastasis staging of the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC) suggest obtaining at least 7-14 lymph nodes in radical resections.6 The number of lymph nodes retrieved could be affected by several factors. The extent of surgery and the examining pathologist could influence the number of lymph nodes.7-9 Even in similar surgical specimens, the number of lymph nodes retrieved could be affected by age, body mass index, tumor location, tumor size, depth of tumor invasion,8, 10-12 lymph node metastasis,13, 14 and preoperative concurrent chemoradiotherapy (CCRT).3, 10, 15 Identifying high risk factors that could decrease lymph node retrieval would be valuable for accurate nodal staging, since other techniques could be used to harvest lymph nodes for high-risk patients.

The aim of this study was to identify risk factors associated with a failure to harvest adequate lymph nodes for accurate nodal staging and to define the impact of CCRT on the number of lymph nodes retrieved in patients who underwent curative radical surgery for mid-low rectal cancer.

Data from 277 patients who underwent radical surgery with curative intention for mid-low rectal cancer between January 1998 and December 2007 were retrospectively analyzed. All patients had histologically proven adenocarcinoma located on the mid to low rectum, within 10 cm from the anal verge. The retrospective review of each patient's medical records yielded clinicopathologic information. The number of lymph nodes harvested was derived from the pathologic report. Distant metastasis was diagnosed by clinical, radiologic examination (abdominopelvic computed tomography, chest computed tomography, pelvic magnetic resonance imaging, positron emission tomography or positron emission tomography-computed tomography), or intraoperative observation and pathologic confirmation. The tumors were categorized according to AJCC 7th edition. Patients with synchronous distant metastasis were included in the analysis if radical surgery with curative intention was performed.

All patients underwent curative radical surgery based on standardized technique and principle, which did not change significantly during the study period. In all patients, surgery included total mesorectal excision with adequate resection margin and regional lymph node dissection with ligation of the inferior mesenteric artery at its origin. For surgery, low anterior resection was normally done. However, in cases where the distal resection margin was not secure, ultra low anterior resection with coloanal anastomosis or abdominoperineal resection was performed instead. Resected specimens were evaluated for depth of tumor invasion, lymph node involvement, histologic type, lymphovascular invasion and resection margins according to standard pathologic evaluation. A careful manual lymph node dissection technique was used to harvest regional lymph nodes. Mesenteric fat clearance technique using chemicals was not used in this study.

Of the 277 patients, 195 (70.4%) underwent radical surgery without preoperative CCRT, and 82 (29.6%) underwent radical surgery after preoperative CCRT. Patients with tumor invasion to mesorectal fascia or adjacent organ and lymph node metastasis on preoperative staging studies or with tumors within 5 cm of the anal verge received preoperative CCRT. The schedule and technique at our institute was as follows. A total of 5040 cGy radiation was delivered in 25 fractions of 180 cGy/day over 5 weeks. Concurrent chemotherapy was administered with intravenous or oral fluorouracil in all the patients. Intravenous 5-FU (425 mg/m²) and leukovorin (20 mg/m²) was administered for 5 days in a continuous manner during the first and fifth weeks of radiotherapy. Otherwise, oral doxifluridine (900 mg/m², Furtulon, Roche, Seoul, Korea) and leukovorin (30 mg/day) were administered during the entire course of radiotherapy. Radical surgery was performed around 6-8 weeks after completing radiation therapy.

Statistical analysis was performed with the statistical package SPSS for Windows (version 12.0 SPSS Inc., Chicago, IL, USA). The Student's t-test was used to analyze the statistical differences in lymph node retrieval between the surgery alone and preoperative CCRT groups, and applied to continuous variables. The χ²-test was used for categorical variables. Multivariate analysis using a multiple linear regression model was used to identify independent variables influencing lymph node retrieval. A value of p<0.05 was considered statistically significant.

The number of lymph nodes retrieved is one reference point to estimate the diagnostic accuracy of nodal staging after curative resection of rectal cancer. In the current study, preoperative CCRT was independently associated with the number of lymph nodes retrieved. In addition, BMI and regional lymph node metastasis were independent contributing factors for the number of lymph nodes retrieved in patients who received preoperative CCRT.

An adequate number of examined lymph nodes is crucial for accurate staging, especially in patients without regional lymph node metastasis.3, 4, 14, 16 Moreover, not examining enough lymph nodes could be associated with poor prognosis because of the chance of understaging the tumor.12 For this reason, the AJCC and UICC recommend harvesting at least 12 negative nodes in the surgical specimen of node negative patients to confirm adequate nodal staging. However, the number of lymph nodes retrieved varies in rectal cancer patients due to several factors. Using at least 12 nodes as the standard, Baxter, et al.10 found only 20% of patients who underwent preoperative CCRT had adequate lymph node staging. We found only 24.4% of patients who underwent preoperative CCRT had adequate lymph node staging, although 52.4% of total patients had adequate lymph node staging.

Preoperative CCRT has become a standard treatment in managing advanced rectal cancer,17 since it decreases the risk of local recurrence,18 improves the prognosis of advanced rectal cancer patients, and facilitates radical excision of T4 cancer and sphincter saving surgery.19 However, one issue is that after preoperative CCRT, surgical specimens often do not contain enough lymph nodes to reach the recommended standard.10, 15, 20 In the current study, preoperative CCRT was an independent risk factor to decrease lymph node retrieval. Moreover, when we looked at tumors treated with preoperative CCRT, lymph nodes retrieved were significantly low in node negative tumors. Thus, there is a chance of understaging, especially in node negative patients.21, 22 However, there may be no association between lymph node retrieval in patients treated by preoperative CCRT and curative surgery with negative lymph node metastasis, and overall survival and disease-free survival.12, 23, 24 After preoperative chemoradiation, retrieved lymph nodes could also be decreased from the therapeutic effect of radiation, resulted in the sterilization of cancer cell and fibrosis in the lymph nodes. If that was the case, then the reduced number of examined lymph nodes is caused by therapeutic effect of preoperative chemoradiation and there would be no effect on patients' survival. However, the clinical impact of reduced lymph nodes after preoperative chemoradiation is still being debated and should be clarified with further study.

Manual lymph node dissection is the current standard at most institutions, and was also used in the present study. Since 1938, when the fat clearance technique was first used,25 other similar methods have been developed to isolate lymph nodes in surgical specimens. Although there has been variation in consistency among the different methods regarding harvesting and processing of lymph nodes, the fat clearance technique could be used for patients at risk of understaging.26, 27 If patients received preoperative CCRT or fewer than 12 lymph nodes were retrieved from the surgical specimens by manual lymph node dissection, the fat clearance technique could be available to increase the staging accuracy.26-28 A multivariate model of the present study revealed that in patients of the CCRT group with higher BMI, fewer lymph nodes were retrieved. For such patients, the fat clearance technique might deserve special consideration.

The current study included rectal cancer within 10 cm from the anal verge, since lymph node yield could be influenced by tumor localization or specimen length.8, 13 Colonic bowel segments bear significantly more lymph nodes than rectal bowel segments, possibly because of a longer mesenteric radix. In the present study, specimens from patients receiving CCRT were longer than in patients who received surgery alone, since we carried out an anastomosis with unirradiated bowel by removing all the sigmoid colon to avoid adverse effects and improve bowel function.29 The number of retrieved lymph nodes was significantly lower in patients who underwent preoperative CCRT despite the longer specimens. This is explained by the high radiosensitivity of lymphoid tissue; lymphocytes can die within hours of radiotherapy without cell division, whereas tumor cells need more time.30-32

In conclusion, preoperative CCRT was an independent variable influencing lymph node retrieval after surgery for mid-low rectal cancer. In patients receiving CCRT before surgery, lower BMI and regional lymph node metastasis were independent variables, increasing lymph node retrieval.