Download Abstract Background: It is unclear whether the number or distribution

Abstract
Background: It is unclear whether the number or distribution of lymph node metastases
can provide a more accurate prognosis. The aim of this study was to evaluate the
prognostic impact of inferior mesenteric artery (IMA) lymph node metastasis (LNM) in
sigmoid colon and rectal cancer.
Methods: We included 188 patients who underwent curative resection for stage III
sigmoid colon and rectal cancer between January 2001 and December 2012. Patients
were divided into two groups based on the presence of IMA LNM (LNM-positive vs.
LNM-negative group). Clinicopathological characteristics, 3-year recurrence-free
survival and 5-year overall survival rates, and recurrence patterns were compared
between the two groups.
Results: Of 188 patients, nine patients (4.79%) were in the LNM-positive group. After
curative resection, 3-year recurrence-free survival and 5-year overall survival rates were
significantly lower in the LNM-positive group compared to the LNM-negative group
(44.44% vs. 69.98%, p = 0.016 for 3-year recurrence-free survival and 48.61% vs.
81.73%, p = 0.018 for 5-year overall survival). Multivariate analysis revealed that the
presence of IMA LNM (p = 0.04), not the number of LNMs (p = 0.153), was an
independent prognostic factor for recurrence-free survival. The paraaortic lymph node
metastasis rate was significantly higher in the LNM-positive group (p = 0.0078).
Conclusions: IMA LNM is an independent predictor of survival for stage III sigmoid
colon and rectal cancer patients. Evaluation of IMA LNM enables accurate estimation
of patient prognosis and enhances appropriate postoperative therapy.
Keywords: Lymph node metastasis・Inferior mesenteric artery・Prognostic factor・
Colorectal cancer.
Introduction
The presence of regional lymph node metastasis is an important prognostic factor after
curative resection for colorectal cancer. This factor defines the tumor stage and
determines the postoperative therapy. According to the guidelines of the TNM
Committee of the International Union Against Cancer (UICC, seventh edition), only the
number of lymph node metastases defines N classification; the distribution of lymph
node metastasis is not taken into consideration.1,2 This TNM staging system has the
advantage of simplicity and has been adopted as a standard worldwide.
A recent study revealed that the anatomical location of lymph node metastasis is
also an important factor for accurate diagnosis.3-6 Kang et al. demonstrated that inferior
mesenteric artery (IMA) lymph node metastasis is associated with a high incidence of
systemic recurrence and poor prognosis after curative resection of colorectal cancer.7
Moreover, Huh et al. showed that the distribution of lymph node metastasis is an
independent predictor of survival for patients with colorectal cancer.8 They stated that
evaluating the distribution of regional lymph node metastases may be helpful for
accurate prognostic stratification and appropriate postoperative therapy. By contrast,
however, Suzuki et al. and others demonstrated that the number, not location, of lymph
node metastases better predicts prognosis for colon cancer.9-11 Thus, whether the
distribution of regional lymph node metastases provides a more accurate prognosis is
subject to debate. Moreover, few studies have focused on IMA lymph node metastasis,
because dissecting the IMA lymph node generally requires complicated surgery and
because the incidence of IMA lymph node metastasis is very low.
Therefore, the purpose of this study was to investigate the prognostic significance
of IMA lymph node metastasis for patients with stage III sigmoid colon and rectal
cancer after curative resection.
Materials and Methods
Patients and Study design
From January 2001 to December 2012, data from 953 consecutive patients who
underwent surgical resection for carcinoma of the sigmoid colon or rectum at our
institute were reviewed. Of these, only patients who underwent curative resection and
had been diagnosed with pathologically curative stage III carcinoma of the sigmoid
colon or rectum were included in this study. Patients were excluded if they had had
preoperative chemotherapy or radiotherapy. Consequently, a total of 188 patients were
included in this study. We defined IMA lymph nodes as a regional lymph node that lies
along the IMA, from the origin of the IMA to the bifurcation of the left colic artery.
Patients were divided into two groups based on the presence of IMA lymph node
metastasis: positive IMA lymph node metastasis (LNM-positive group) and negative
IMA lymph node metastasis (LNM-negative group). Clinicopathological characteristics,
3-year recurrence-free survival and 5-year overall survival rates, and recurrence patterns
were compared between the two groups. All patients provided written informed consent,
in accordance with guidelines approved by the Institutional Review Board of Ethics at
our institute, in accordance with the Declaration of Helsinki.
Surgical Technique
All patients who were included in this study underwent curative resection for their
primary tumors, according to surgical oncological principles, and total mesorectal
excision was performed by experienced surgical experts who are board certified
surgeons in gastroenterology by The Japanese Society of Gastroenterological Surgery.
All regional lymph nodes were dissected, including IMA lymph nodes. The inferior
mesenteric vein was ligated and divided. Distal surgical margins of >5 cm were
achieved for tumors located above the peritoneal reflection, and surgical margins were
>2 cm for tumors located below the peritoneal reflection. Lateral pelvic lymph node
dissection was not performed routinely in the surgical procedure. The primary tumor
and all dissected lymph node specimens were stained with hematoxylin and eosin and
evaluated by experienced pathologists. Pathological stages were determined according
to the seventh edition of the UICC TNM Classification of Malignant Tumors.2
Following curative resection of the tumor, patients underwent blood tests including
tumor marker CEA and CA19-9 every 3 months, chest-abdominal computed
tomography every 6 months, and colonoscopy annually.
Statistical Analysis
Statistical analyses were performed using the JMP10 program (SAS Institute, Cary, NC,
USA) and GraphPad Prism version 6.00 for Windows (GraphPad Software, San Diego
CA, USA). Factors between the two groups were compared using chi-square test and
Fisher’s exact test, and continuous variables were compared with Student’s t-test.
Survival rates were calculated using the Kaplan–Meier method. After univariate
analysis of the potential predictive factors affecting recurrence-free survival and overall
survival, only the significant variables were used in the multivariate analysis, which
used the Cox proportional hazard model and the log-rank test to calculate hazard ratios
(HR) and 95% confidence intervals (CI). Analysis data are expressed as mean ±
standard deviations, and two-tailed p values < 0.05 were considered statistically
significant.
Results
Clinicopathological Characteristics
Clinicopathological characteristics between the two groups are shown in Table 1. IMA
lymph node metastasis (LNM-positive group) was observed in nine patients (4.79%),
whereas 179 patients (95.21%) had no IMA lymph node metastasis (LNM-negative
group). Although the number of retrieved lymph nodes was not significantly different
between the two groups, the number of metastatic lymph nodes was significantly higher
in the LNM-positive group than in the LNM-negative group (p < 0.001). No significant
differences were found in sex, age, preoperative carcinoembryonic antigen (CEA)
levels, tumor size, tumor location, tumor invasion, histological grade, nor postoperative
adjuvant chemotherapy. The patients in each group received exactly the same adjuvant
chemotherapy. In LNM-positive group, 7 out of 9 patients (77.8%) received 5fluorouracil (5-FU) based adjuvant chemotherapy. Among these 7 patients, 2 patients
(28.6%) received 5-FU plus oxaliplatin based adjuvant chemotherapy. In the LNMnegative group, 137 out of 179 patients (76.5%) received 5-FU based adjuvant
chemotherapy. Within these 137 patients, 13 patients (9.5%) received 5-FU plus
oxaliplatin based adjuvant chemotherapy. Importantly, the ratio of the patients who
received 5-FU based adjuvant chemotherapy in each group was statistically the same (p
= 1.00, analyzed by Fisher's exact test). However, 44 patients did not receive adjuvant
treatment due to poor performance status or patient refusal.
Survival Analysis
With a median follow-up period of 981 days, the 3-year recurrence-free survival rate
was significantly lower in the LNM-positive group than in the LNM-negative group
(44.44% vs 69.98%, respectively; p = 0.016) (Fig. 1). Moreover, with a median followup period of 1499 days, the 5-year overall survival rate was also significantly lower in
the LNM-positive group than in the LNM-negative group (48.61% vs 81.73%,
respectively; p = 0.018) (Fig. 2).
Clinicopathological Factors Associated with Poor Prognosis
Univariate analysis indicated that the clinicopathological factors associated with poor
recurrence-free survival were tumor size (p = 0.002), tumor invasion (p = 0.0003), and
IMA lymph node metastasis (p = 0.046). Multivariate analysis revealed that IMA lymph
node metastasis was an independent prognostic factor (p = 0.04), in addition to tumor
size (p = 0.035) and tumor invasion (p = 0.006) (Table 2). However, the number of
metastatic lymph nodes was not associated with poor prognosis in this patient
population (p = 0.153). For overall survival, the preoperative CEA level was the only
factor associated with poor prognosis (p = 0.027) (Table 3).
Primary Recurrence Pattern
Among the various primary recurrence patterns, the paraaortic lymph node metastasis
rate was significantly higher in the LNM-positive group than in the LNM-negative
group (33.3% vs 3.91%, respectively; p = 0.0078) (Table 4). The median interval of
paraaortic lymph node recurrence was 480 days after curative resection. In other
primary recurrence patterns, no significant differences were found between the two
groups.
Discussion
The present study revealed that the survival rate was significantly lower in the LNMpositive group than in the LNM-negative group. The reasons for this poorer prognosis
could be the larger number of metastatic lymph nodes and the higher rate of paraaortic
recurrence in the LNM-positive group. Moreover, IMA lymph node metastasis was an
independent poor prognostic factor for patients with stage III sigmoid colon and rectal
cancer. Multivariate analysis indicated that the number of metastatic lymph nodes was
not an independent prognostic factor in this study. These results support the concept that
the distribution, rather than the number of lymph node metastases, is a valuable and a
reliable prognostic factor for patients with colorectal cancer.8,12,13 Furthermore, the
present study yielded a reasonable average number of retrieved lymph nodes: 21.94 per
patient. Indeed, the American Joint Committee on Cancer and other reports have
recommended that 12 or more lymph nodes should be retrieved in patients with
colorectal cancer who undergo curative intent surgery.1,14,15
A recent prospective study by Leibold et al. suggested that the current TNM staging
system, based on the number of metastatic lymph nodes alone, may not provide an
accurate assessment, especially after preoperative chemoradiotherapy.16 Because the
number of involved lymph nodes decreases after preoperative treatment, the authors
stated that the staging system should incorporate the distribution as well as the number
of metastatic lymph nodes. Moreover, Kang et al. reported that the 5-year disease-free
survival rate was lower in the positive IMA lymph node metastasis group than in the
negative IMA lymph node metastasis group (31.9% vs 69.4%, respectively; p < 0.001).7
They demonstrated that IMA lymph node metastasis was associated with a high
incidence of systemic recurrence, and that it was an independent prognostic factor after
curative resection of stage III sigmoid or rectal cancer patients. Consequently, in this
context, the current Japanese Classification of Colorectal Carcinoma (eighth edition) is
based on both the presence of IMA lymph node metastasis and the absolute number of
metastatic lymph nodes.17
Although several reports have suggested the prognostic significance of IMA lymph
node metastasis in colorectal cancer, the appropriate region of elective lymph node
dissection has not been established. According to our results, IMA lymph node
metastasis was significantly associated with paraaortic lymph node recurrence, because
they are anatomically close and connected through lymphatic vessels. Furthermore, a
previous study demonstrated the high incidence of systemic recurrence in patients with
IMA lymph node metastasis.7 These findings may support the survival benefits of
removal of IMA lymph nodes by high ligation.18 In addition, Kanemitsu et al. evaluated
1188 consecutive patients who underwent resection for sigmoid colon or rectal cancer,
with high ligation of the IMA.19 They demonstrated that high ligation of the IMA
allowed curative resection and long-term survival. By contrast, recent systematic
reviews reported that there is no survival benefit to removal of IMA lymph nodes by
high ligation.20 This surgical procedure decreases perfusion and innervation of the
proximal limb, increasing the risk of anastomotic leakage.21 Moreover, the incidence of
IMA lymph node metastasis was 4.79% in our study and was reported in previous
studies to be low, ranging from 0.3% to 8.6%.16,20,22,23 This low incidence could also be
one of the reasons that we and others could not demonstrate a survival benefit. Taken
together, there is no conclusive evidence to support a survival benefit among patients
who undergo removal of IMA lymph node by high ligation.24-26 However, our results
suggest that pathological evaluation after dissection of the IMA lymph node is
necessary for appropriate tumor staging and accurate estimation of patient prognosis.
Moreover, these results would be beneficial in determining appropriate postoperative
treatment strategy. The patients with positive IMA lymph node metastasis should be
carefully followed up with tumor biomarkers as well as imaging modalities, and should
be highly recommended to receive 5-FU plus oxaliplatin based adjuvant chemotherapy
intensively.
There are several limitations to this study. First, the number of patients who had
IMA lymph node metastasis was relatively small in this study, which is similar to other
studies. Second, patients with either sigmoid colon cancer or rectal cancer were
included in this study, although these two cancers have generally different biological
behaviors, especially different drainage basins of the lymph nodes. However, there was
no significant difference in tumor location between the two groups and multivariate
analysis revealed that IMA lymph node metastasis was prognostically significant,
regardless of the tumor location. Third, advances and changes in chemotherapy since
2001 could have some impact on patient survival in this study. However, the baseline
ratio of patients who received 5-FU based adjuvant chemotherapy in each group was
statistically the same, and thus enabled us to perform fair comparisons between the two
groups. Further studies are needed to evaluate the impact of IMA lymph node metastasis
on survival in order to yield the best outcomes for patients with colorectal cancer.
In conclusion, our study revealed that IMA lymph node metastasis is an
independent poor prognostic factor for patients with stage III sigmoid colon and rectal
cancer after curative resection. Pathological evaluation of IMA lymph node metastasis
enables accurate estimation of patient prognosis and enhances appropriate postoperative
therapy.
Conflict of Interest
All authors have no potential conflicts of interest to disclose.
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Figure Legends
Figure 1. Kaplan–Meier recurrence-free survival in LNM-positive and LNM-negative
groups. The 3-year recurrence-free survival rates of the LNM-positive group and the
LNM-negative group were 44.44% and 69.98%, respectively (p = 0.016).
Figure 2. Kaplan–Meier overall survival in LNM-positive and LNM-negative groups.
The 5-year overall survival rates of the LNM-positive group and the LNM-negative
group were 48.61% and 81.73%, respectively (p = 0.018).
Table 1. Clinicopathological characteristics
SD, standard deviation; RS, rectosigmoid; Ra, above peritoneal reflection; Rb, below
peritoneal reflection; No, number; well, well differentiated; mod, moderately
differentiated.
Table 2. Univariate and multivariate analyses for recurrence-free survival
RR, relative risk; CEA, carcinoembryonic antigen; LN, lymph node; IMA, inferior
mesenteric artery; well, well differentiated; mod, moderately differentiated.
Table 3. Univariate and multivariate analyses for overall survival
RR, relative risk; CEA, carcinoembryonic antigen; LN, lymph node; IMA, inferior
mesenteric artery; well, well differentiated; mod, moderately differentiated.
Table 4. Primary recurrence patterns
LN, lymph node.