Potential Prognostic Benefit of Lateral Pelvic Node Dissection for Rectal Cancer Located Below the Peritoneal Reflection

Abstract

Objective:

To identify the parameters related to the effective selection of patients who could receive prognostic benefit from lateral pelvic node dissection.

Background:

Accurate preoperative diagnosis of lateral nodal involvement (LNI) remains difficult, and the indications for lateral lymph node dissection have been controversial.

Patients and Methods:

A total of 244 consecutive patients who underwent potentially curative surgery with lateral dissection for advanced lower rectal cancer (1985–2000) were reviewed. Patients were stratified into groups based on various parameters, and the therapeutic value index for survival benefit was compared among groups. The therapeutic index of lateral dissection was calculated by multiplying the frequency of metastasis to the lateral area and the cancer-related 5-year survival rate of patients with metastasis to the lateral area, irrespective of metastasis to other areas (mesorectal, superior rectal artery [SRA], and inferior mesenteric artery [IMA] areas).

Results:

LNI was observed in 41 patients (17%); and 88% of them had nodal involvement in the region along the internal iliac/pudendal artery or in the obturator region (“vulnerable field”). The cancer-related 5-year survival rate among the patients with LNI was 42%; the therapeutic index for lateral dissection was calculated as 7.0 patients, which was much higher than that of lymphadenectomy of the SRA area (1.6 patients) and the IMA area (0.4 patients), and almost comparable to that of lymphadenectomy of the upward mesorectal area (6.9 patients). Although it was possible to select groups at high and low risk for LNI based on several parameters related to tumor aggressiveness, such as tumor differentiation in biopsy specimens, the therapeutic value index was not significantly different between these groups. Unlike these parameters, the diameter of the largest lymph node in the “vulnerable field,” which was positively correlated with the rate of LNI but irrelevant to the prognosis, was able to successfully stratify patients by therapeutic index.

Conclusions:

Advanced lower rectal cancer patients having LNI in the lateral pelvic area are likely to receive prognostic benefit from lymphadenectomy. The most efficient means of determining the effectiveness of lateral dissection preoperatively is to estimate the nodal diameter in the “vulnerable” lateral regions by diagnostic imaging.

Among 244 patients who underwent potentially curative surgery with lateral pelvic node dissection for advanced lower rectal cancer, lateral nodal involvement (LNI) was observed in 41 patients (17%), and 88% of them had nodal involvement in the region along the internal iliac/pudendal artery or in the obturator region (“vulnerable field”). The cancer-related 5-year survival rate of patients having LNI was 42%; the therapeutic value of lateral dissection was much higher than that of lymphadenectomy of the superior rectal artery (SRA) region. In terms of the prognostic benefit of lateral dissection, patients could be stratified most efficiently based on the nodal diameter in the “vulnerable” lateral regions.

A major recurrence pattern after surgery for lower rectal cancer is pelvic recurrence, which imposes a severe burden on patients, effectively ruining their quality of life. The most important parameter affecting the postoperative survival after curative operation is the extent of lymphatic spread, by which advanced rectal cancer patients can be divided into those with disease defined in the mesorectum and those with extramesorectal lymphatic spread, such as lateral pelvic node involvement. The concept of mesorectal clearance, ie, eradication of the disease in the mesorectum, is the basis of lower rectal cancer surgery and has promoted widespread application of the technique of total mesorectal excision (TME). In Western countries, TME, which has been associated with good prognosis^1–4 and low morbidity,⁵ is now regarded as the standard procedure for advanced lower rectal cancers.¹ On the other hand, as a matter of course, extramesorectal metastases, such as lateral nodal involvements, are not removed by the TME technique. The strategy available at present to treat the extramesorectal disease is TME combined with radiotherapy^6–9 or lateral pelvic lymphadenectomy.

Although the recognition of lateral lymphatic drainage system in patients with rectal cancer dates back to the 1930s,^10–12 and Western surgeons attempted lateral dissection as early as the 1950s to improve postoperative survival,^13–15 this procedure is currently favored only in Japan. With regard to the therapeutic value against extramesorectal disease, few reports have addressed the survival benefit produced by TME plus radiotherapy; on the other hand, it has been demonstrated that lateral dissection results in a 5-year survival of 25% to 50% for patients with pathologically proven lateral nodal involvement.^16–19 However, the validity of lateral dissection for all patients with advanced lower rectal cancer, including patients with preoperative imaging showing no definite lateral nodal involvement, is inconclusive, as Western surgeons have often pointed out, because of the lack of randomized controlled studies including a sufficient number of patients.^20,21

The indications for lateral dissection as a treatment of rectal cancer have been controversial in Japan since the 1980s, when the procedure was first reported to have a favorable prognostic outcome. One of the most important matters in this field is that a precise preoperative diagnosis of lateral nodal involvement remains difficult, and the prophylactic lateral dissection should produce morbidity, including urinary and sexual dysfunction,^8,22 in patients having no actual lateral metastases. Some risk factors of lateral involvement related to tumor aggressiveness, such as the status of mesorectal nodes²³ and tumor grade,^23,24 have been reported, and these are often regarded as candidate criteria for lateral dissection. However, there have been few reports on the appropriateness of lateral dissection for the treatment of highly aggressive tumors.

In the present study, we reviewed and analyzed the prognostic data of patients who underwent lateral dissection in one institute where this procedure has been performed persistently, and made an attempt to clarify two clinically important issues. The first was the question of where the lateral lymph node area should be placed as the target region of lymphadenectomy. Then we evaluated the prognostic value of lateral nodal dissection in comparison with the benefit of lymphadenectomy for other lymph node areas. Second, we considered which indicators would be most effective in determining the subset of patients who would receive actual prognostic benefit from lateral nodal dissection. The concept of the therapeutic value index, which was first proposed by Sasako et al²⁵ as a means of evaluating the “weight” of lymph node stations in gastric cancer patients, is introduced to deal with these 2 issues.

PATIENTS AND METHODS

Patients

From 1985 to 2000, 455 patients underwent laparotomy at the National Defense Medical College Hospital for their advanced rectal cancers (cancers penetrating into or through the muscularis propria layer) located below the peritoneal reflection (ie, in the lower rectum). In this period, systematic lateral dissection was generally indicated for patients having rectal cancers located below the peritoneal reflection whose tumor penetrated the rectal wall on the basis of preoperative images (barium enema, endoscopy, and endoluminal ultrasonography), digital examination, or intraoperative manipulation, or whose tumor was limited to the muscular layers but whose nodal involvement was evidenced by the preoperative images (computed tomography and/or magnetic resonance imaging and endoluminal ultrasonography) or intraoperative manipulation. Among the 455 patients, 87 patients had distant metastases. Among the remaining 368, who were potential candidates for lateral dissection based on final tumor stage, 90 patients (24.5%) did not receive systematic lateral dissection because of the patient's surgical risk or mistaken preoperative staging. In addition, the following were excluded from this study: patients with tumors whose circumferential surgical margin was judged as pathologically positive (25 patients), patients with preoperative adjuvant therapy (5 patients), and patients without follow-up of more than 3 years (4 patients). Therefore, 244 patients having advanced rectal cancer located below the peritoneal reflection, who underwent potentially curative surgery with systematic lateral dissection, were reviewed in the present study. No patients received postoperative radiation therapy or intensive intravenous chemotherapy.

Division of Lateral and Mesorectal Areas and Surgical Procedure

By slight modification to the Japanese Classification of Colorectal Carcinoma,²⁶ the regional area of the lower rectum was classified into four areas, ie, the mesorectal area, superior rectal artery (SRA) area, inferior mesenteric artery (IMA) area, and lateral area (Fig. 1). The mesorectal area was further divided into two regions: the mesorectum (adjacent) region (tumor-level mesorectum, distal-side mesorectum, and proximal-side mesorectum within 5 cm from the oral edge of the main tumor) and the mesorectum (distant) region (proximal-side mesorectum 5 cm or more away from the tumor). The lateral area, ie, the iliac lymph node area outside of the mesorectum, was divided into the following six regions: 1) the internal pudendal (outside of the pelvic plexus), 2) the internal iliac (proximal to the superior vesical artery), 3) the common iliac, 4) the external iliac, 5) the obturator, and 6) the presacral regions. The IMA area was defined as the area around the IMA between the origin of IMA and the origin of the LCA (left colic artery) and was distinguished from the SRA area.

FIGURE 1. Division of the removed lymph nodes of lower rectal cancer. The lymph node field was divided into the mesorectal area, SRA area, IMA area, and lateral area. The level of 5 cm proximal from the oral edge of the primary tumor formed the boundary between the mesorectum (adjacent) region and mesorectum (distant) region. The lateral area was composed of 6 regions. The superior vesical artery stood on the boundary between the internal iliac region and the internal pudendal region.

The surgical procedures used for the 244 patients included in the present study were as follows: abdominoperineal resection (139 patients), anterior resection (90), total pelvic exenteration (11), Hartmann's procedure (2), and abdominosacral resection (2). Lateral dissection was performed after en bloc resection of the rectum, total mesorectum with visceral pelvic fascia, and the lateral sidewall structures including the pelvic nerve plexuses. Ligation of the root of IMA (high-ligation) was performed for the complete lymphadenectomy in the IMA area in 225 patients (92.2%); and ligation of just below the origin of LCA (low-ligation) with total dissection of the SRA area was performed for the others. After finishing resection of the rectum together with the IMA, SRA, and mesorectal areas, lateral dissection (en bloc removal of fatty tissue in the respective lateral regions by using a sharp incision technique under direct vision) was performed.¹⁷ When nodal involvement existed grossly in the internal pudendal region or obturator region, extended lymphadenectomy as reported by Moriya et al,¹⁹ ie, iliac lymphadenectomy with en bloc dissection of the internal pudendal vessels, preserving both the superior vesical artery and the obturator nerve, was carried out (Fig. 2).

FIGURE 2. Extended lymphadenectomy of the lateral area. En bloc removal of lymph nodes in the 6 re-spective lateral regions. The internal pudendal vessels (arteries and/or veins) were resected together with the fatty tissue of the internal pudendal region. *Stump of the internal pudendal artery.

Method of Analysis

To define for each area what proportion of patients may have derived benefit from removal of the nodes involved, the therapeutic value index was calculated by multiplying of the frequency of metastasis to the area and the cancer-related 5-year survival rate of patients with metastasis to the area, irrespective of metastasis to other areas.²⁵ First, the therapeutic value index was compared among the lymph node areas defined above, to clarify the optimal position of the lateral area in terms of the benefit of lymphadenectomy. Second, the patients were classified according to various parameters that could be evaluated preoperatively or intraoperatively, and the therapeutic index scores of the lateral area were compared among these groups to determine the population most likely to obtain actual prognostic benefit by lateral dissection.

Parameters Examined

Baseline parameters consisted of following variables: age, sex, tumor location (level of tumor distal edge), diameter of tumor, annularity, depth of tumor penetration, nodal state, and histology of endoscopic biopsy. These had been recorded in the pathologic reports according to the Japanese Classification of Colorectal Carcinoma.²⁶

The diameter of lymph nodes in the lateral area, which were fixed with 20% formalin, was also evaluated on the slide glass. The largest lymph node, irrespective of metastasis, was chosen in each lateral division on the slide, and the average diameter of the short axis and the long axis (D) was determined. When the tumor deposit having no lymph node structures was larger than any lymph node in the division, the short and long axis of the tumor deposit including the surrounding connective tissue was measured. No immunohistochemical techniques were used to identify nodal metastasis in the present study.

RESULTS

Incidence and Prognostic Impact of Lateral Nodal Involvement

Lateral nodal involvement was observed in 41 patients (16.8%), in whom 10 patients had no nodes involved in the mesorectum. The lateral region that showed the highest rate of nodal involvement was the internal pudendal artery region, followed by the internal iliac artery region and obturator region (Table 1). Among the patients with lateral nodal involvement, 87.8% had positive nodes in one or more of these three regions (“vulnerable field”).

TABLE 1. State of the Lymph Nodes in the Respective Lateral Regions

The 5-year survival rate in patients having lateral nodal involvement was 41.6%, and their accumulative local recurrence-free 5-year survival rate was 59.0% (Fig. 3). Patients who had positive lateral nodes but no nodes in the mesorectum had a 5-year survival rate of 78.7%. The therapeutic value index for survival benefit and the local control benefit by lateral dissection were calculated to be 7.0 points (16.8 × 0.416) and 9.9 points (16.8 × 0.590), respectively. These values were comparable to the therapeutic index scores of lymphadenectomy of the mesorectum (distant) region dissection, and much higher than those obtained by lymphadenectomy of the SRA area and those obtained by lymphadenectomy of the IMA area (Table 2).

FIGURE 3. Cancer-specific and local recurrence-free survival of patients with nodal involvement in the lateral pelvic area.

TABLE 2. Therapeutic Value Indexes by the Lymph Node Dissection of the Respective Lymph Node Areas

Size of the Lymph Nodes in the Lateral Region

The number of lymph nodes in the lateral region was the highest in the obturator region (6.9 ± 5.5), followed by the external iliac artery region (4.5 ± 4.4) (Table 1). The nodal size varied widely among lateral regions when it was examined in patients without lateral nodal involvement, ie, it was the largest in the external iliac region (D = 6.6 ± 2.6 mm) and the smallest in the internal iliac region (D = 3.5 ± 1.6 mm).

In all regions of lateral area, the diameter of the largest lymph node was statistically larger in patients with positive lateral nodes than in those without lateral nodal involvement (Table 1). When we analyzed the size of the largest nodes in the “vulnerable field,” D was 6.0 ± 2.8 in patients with no lateral nodal involvement and 8.5 ± 4.1 in patients having lateral nodal involvement (P < 0.0001).

Risk Factors of Lateral Nodal Involvement and Their Clinical Implication for Prognostic Outcome After Lateral Dissection

The tumor diameter, as well as the sex and the patient's age, had no significant impact on the incidence of lateral nodal involvement. The preoperative CEA level and the annularity had a marginal impact on the incidence of lateral nodal involvement (Table 3).

TABLE 3. Risk Factors for Lateral Nodal Involvement

The incidence of lateral nodal involvement had a significant correlation with the level of the tumor distal edge, tumor penetration depth, number of involved nodes in regions other than the lateral area, nodal involvement in the SRA region, and endoscopic biopsy histology (Table 3). However, patients classified in the high-risk group of lateral nodal involvement tended to have a lower 5-year survival rate compared with the low-risk group, and none of these parameters was able to divide patients with significantly different therapeutic value index scores (Table 4).

TABLE 4. Therapeutic Value Indexes of Lateral Nodal Dissection by Risk Parameters of Lateral Nodal Involvement

The diameter of the largest lymph node in the “vulnerable field” was correlated with the incidence of nodal involvement (Table 5). Namely, the incidence of lateral nodal involvement was only 3.5% in patients with a value of D ≤ 5 mm, whereas it was 16.1% in those for whom 5 mm < D < 10 mm, and it was 34.0% in those with a value of D ≥ 10 mm. However, unlike the parameters mentioned above, the lymph node diameter had no adverse impact on the postoperative survival, but it successfully divided patients according to their therapeutic value index; ie, the survival benefit index was 1.3 points in the D ≤ 5 mm group, 9.8 points in the 5 mm < D < 10 mm group, and 13.4 points in the D ≥ 10 mm group, respectively. In the same way, nodal size in the “vulnerable field” could divide patients with different therapeutic value index scores of local control.

TABLE 5. Therapeutic Value Indexes of Lateral Dissection by the Diameter of the Lymph Nodes in the Lateral Area

DISCUSSION

The incidence of lateral nodal involvement in lower rectal cancer patients has been reported as 16% to 23%.18,19,22,23,27,28 Further studies will be needed to clarify the discrepancy between these figures and the rate of local recurrence after TME, which has been reported as around 5%,^1,2,29 but we can say that the lateral area, and especially the “vulnerable field” (internal pudendal region, obturator region, and internal iliac region), is an important field of cancer spread for rectal cancers located below the peritoneal reflection. The oncologic significance of the lateral pelvic area is also understandable by the observation that extramesorectal regions such as the periphery of the internal iliac artery (the internal pudendal region in this paper) are often very close to the circumferential margin of the primary tumor.

Western surgeons generally have had a negative attitude in regard to systematic lateral pelvic lymphadenectomy,²⁰ including lymphadenectomy of the obturator fossa.³⁰ The UICC staging (6th edition) has placed lymph nodes only in the internal iliac region among lateral area as regional lymph nodes.³¹ With regard to the lateral lymphatic drainage from the lower rectum, there is a theory that it passes through the lateral ligament laterally beyond the mesorectum, and then to ascend along the internal iliac artery and inside the obturator space.¹⁸ In our series, the proportion of patients with positive nodes in the “vulnerable field” amounted to 88% of patients with lateral nodal involvement. The obturator region, where the highest number of nodes was included in the lateral area,³² should be seen in a new light as an important cancer spread region, rather than the common iliac region, in cases of lower rectal cancer.

To determine the optimal extent of lymphadenectomy, it is important to assess what proportion of patients have derived prognostic benefit from lymphadenectomy of the respective lymph node area. The concept of the therapeutic value index, which is obtained simply by the incidence of metastasis and the 5-year survival rates of those having metastasis in that particular lymph node area, irrespective of nodal metastasis to other areas, is introduced in the present study. With regard to the therapeutic value of lateral dissection, the survival benefit index was calculated as 7 points and the local control benefit as 10 points, in cases in which lateral dissection was applied to advanced lower rectal cancer patients without distant metastasis whose preoperative stage was T3, T4, or T2 (N[+]). The data used in the present study included lymph node metastasis based on routine histologic examination using only one section of each lymph node. Because occult metastases exist in lateral pelvic nodes in around 4% of cases, as we demonstrated previously,³³ and micrometastases revealed by cytokeratin staining have been observed in lateral lymph nodes in as many as 19% of cases,³⁴ the evaluation made here indicates the minimum benefit of lymph node dissection.

It is impossible to generalize about the cutoff level of the therapeutic index by which the indication for lymphadenectomy of a particular region should be determined, but, using this index, we can compare lymph node areas in terms of the therapeutic value of node dissection. It is noteworthy that both the survival and local control benefits by lateral dissection were comparable to those obtained by the nodal dissection of the upward mesorectal lymphatic spread and were much higher than those obtained by the dissection of the SRA area where lymphadenectomy was routinely performed in the TME technique. In addition, based on the results of the present study, the prognostic value of high ligation performed in an attempt to remove lymph nodes in the IMA area thoroughly is much lower than that of lymph node dissection of other areas, including the lateral area. The 5-year survival rate of patients with metastatic nodes in the lateral pelvic area, which was removed by radical lymphadenectomy, reached 42% in this series, and this value was almost the same as that from other Japanese institutes where lateral nodal dissection has long been performed consistently (Table 6, in which English-written reports analyzing 40 or more patients with lateral nodal involvement are listed).^19,23,35 This would clearly indicate that lateral nodal involvement is not necessarily a phenomenon of systemic disease and there is a group of patients who derives prognostic benefit from lateral dissection. The Guideline 2000 for Colon and Rectal Surgery mentions that the appropriate level of proximal lymphovascular resection for rectal cancer is at the origin of the superior rectal artery, which is immediately distal to the takeoff of the left colic artery; furthermore, it is clearly mentioned that the dissection should attempt to remove clinically suspected lateral lymph node disease.³⁶ The results of the present study could support this and provide the clinical bases for the content in the guideline.

TABLE 6. Incidence and 5-Year Survival of Patients With Lateral Nodal Involvement by Rectal Cancer Located Below the Peritoneal Reflection

We previously reported that the survival outcome of lateral node-positive patients having 3 or fewer nodes, including nodes involved in the mesorectum, had a 75% 5-year survival rate, whereas patients with 4 or more involved nodes had only a 4% survival rate.¹⁷ It has long been recognized that the lymphatic drainage system of the lower rectum is highly variable individually, and lateral lymphatic drainage is important as the route of metastasis below the middle valve of Houston.¹³ Takahashi et al reported that 16 of 66 patients with lateral nodal involvement had no nodal involvement in the mesorectum and the 5-year survival rate of such patients reached 75%,¹⁸ which were similar to the results in the present study. We can estimate that the lateral area, especially the “vulnerable field,” includes sentinel nodes in some lower rectal cancer patients, and this could be a reason why lateral nodal involvement does not necessarily reflect extensive lymphatic spread. In patients whose lymph node status indicates that the lymph node in the lateral area is the sentinel node, favorable prognosis can be expected by lateral dissection. However, it remains clinically difficult to have an accurate preoperative grasp of the state of nodal involvement, not only in the lateral region but also in the mesorectum.

Under the circumstances, numerous studies in Japan have sought to identify risk factors of lateral nodal involvement as criteria for performing lateral dissection.

Disappointingly, however, the results of the present study suggest that the strategy of stratifying the therapeutic value of lateral dissection based on parameters related to the potential of metastasis is unpromising, since those related to a high-incidence of lateral involvement reflected poorly on postoperative survival. On the other hand, the size of the largest lymph node in such “vulnerable field” had a strong correlation to lateral nodal involvement, and being dissimilar to the parameters related to the tumor's metastatic potential, it had no adverse correlation with prognosis and could stratify patients with different therapeutic values.

CONCLUSION

Preoperative evaluation of the prognostic benefit brought by lateral dissection could be performed most efficiently based on the nodal swelling in the “vulnerable” lateral regions, rather than on the parameters related to the malignant potential in the primary tumors. In other words, parameters related to the tumor's metastatic potential are not adequate as selection criteria for prophylactic lateral dissection and the existence of lateral pelvic lymph nodes that are clinically suspected of having disease would be the indicator to give the greatest clinical value to lateral dissection. The results of the present study underscore the importance of the development of preoperative images, which justify the policy that lateral nodal dissection should be performed only if lateral lymph node swelling is detected.^36,37 Unfortunately, this retrospective study had a limit in determining the actual cutoff size of nodes, which is important clinically, because there was discrepancy between the size on the slide and the size detected in the image for several reasons, including a shrinking effect by fixation. Another issue that must be clarified is to determine the cutoff size of nodes observed in the preoperative images, such as MRI or CT. In addition, a method of lateral dissection for patients with lateral nodal metastasis is not yet established, and in the future we will have to compare prognostic and functional outcomes between the radical surgery routinely performed in our institute, which consists of en bloc resection of both the pelvic nerve plexus and internal pudendal vessels, and lymphadenectomy sparing these structures.^35,38,39 Future studies should also consider a modality for selecting patients to undergo lateral dissection, including modern techniques of sentinel lymph node mapping.⁴⁰