Abstract
Aim
Studies have demonstrated a relationship between lymph node (LN) yield and survival after colectomy for cancer. The impact of surgical technique on lymph node yield has not been well explored.
Method
This is a retrospective study of right colectomies (RC) for cancer at a single institution from 2012–2014. Exclusion criteria were previous colectomy, emergent and palliative operations. All data were collected by chart review. Primary outcomes were LN yield and the lymph node to length of surgical specimen (LN-LSS) ratio. Multivariable mixed models were created with surgeon and pathologist as random effects. Sensitivity analyses were performed to exclude stage IV cancers and to analyze groups on an “as-treated” basis.
Results
We identified 181 open (O-RC), 163 laparoscopic (L-RC) and 119 robotic (R-RC) cases. Open RC was more commonly performed in females with metastatic disease. Mean LN yield was 28, 29, and 34 in O-RC, L-RC, and R-RC, respectively; mean LN-LSS ratios were 0.83, 0.91 and 1.0. The R-RC approach produced a higher LN yield compared to other approaches (p < 0.01), and a higher LN-LSS ratio compared to O-RC (p < 0.01). These findings were unchanged in sensitivity analyses.
Conclusion
Robotic RC improves LN yield and LN-LSS ratio, which may reflect a better mesocolic excision. The effect of these findings on survival requires further investigation.
Introduction
Lymph node (LN) status is the single most important predictor of survival in non-metastatic colorectal cancer.[1, 2] Multiple studies have demonstrated a relationship between the number of lymph nodes retrieved during colectomy and survival. [3–9] Although the American Joint Committee on Cancer (AJCC) recommends a minimum of 12 nodes for adequate staging, an optimal cutoff has yet to be established [5, 10, 11] The Intergroup 0089 trial showed that LN yields of greater than 20 and 35 nodes were associated with better disease-specific survival in node-negative and node-positive patients, respectively.[5] Similarly, the INTACC trial suggested an optimal LN cutoff of 18, though the survival difference was only seen in node-negative patients.[12] Using data from the SEER database, Cserni et al. found that LN yields of up to 40 nodes may be associated with the greatest probability of survival and showed that overall survival increases linearly with each additional retrieved negative node between 1 and 40.[13
Multiple factors, including surgical technique, may impact LN yield in resections for colon cancer.[9, 10, 14–16] To date, studies comparing robotic, laparoscopic and open colectomies have reported conflicting results regarding LN yields. [17–20] As the paradigm for oncologic resections shifts towards increasing LN yields, it is important to assess the role of surgical technique in optimizing lymph node retrieval. The purpose of this study, therefore, was to compare the pathologic outcomes after open (O-RC), laparoscopic (L-RC) and robotic (R-RC) right colectomy for cancer. We hypothesized that with its increased dexterity and visualization, R-RC would lead to higher LN yield and an improved mesocolic excision.
Method
All patients who had a right colectomy (RC) for cancer between January 1, 2012 and December 31, 2014 were identified in the institutional database by CPT and ICD-O codes. Patients were included if they had undergone surgery for a colonic neoplasia and had been operated on by one of six specialized colorectal surgeons. Exclusion criteria were age less than 18, previous colectomy for cancer and pathology other than adenocarcinoma or carcinoid. Patients undergoing additional operative procedures during the index surgery were included as long as these did not involve other intestinal anastomoses. This study was approved by the Institutional Review Board of Memorial Sloan Kettering Cancer Center.
The electronic medical record (EMR) was reviewed by two members of the research team for clinical, demographic, operative and pathological details. Cases were categorized as open (O-RC), laparoscopic (L-RC) and robotic (R-RC) resections on intent to treat basis, according to the CPT code listed for the surgery. In L-RC and R-RC cases, enlarging the extraction site incision for any purpose besides extraction of the specimen was considered a conversion to O-RC. Some surgeons, by convention, mobilized the colon using a minimally invasive approach, then exteriorized the segment for the purposes of vascular ligation, resection and anastomosis; these cases were not considered conversions to open. Resections were considered “extended RC” if the surgeon designated them as such. Information about the ligated vascular pedicle was also gathered from the operative report.
Pathological evaluation of the resected specimen was performed according to standard procedure. Specifically, specimens are sent to pathology fresh right after removal from the patient. The pathologists then open the bowel, take tissue samples for tumor procurement purposes, pin the specimen to a supportive vehicle, and place the specimen in formalin right away. The fixation time is usually 6 hours to overnight. All attached pericolic soft tissues are thoroughly examined for lymph nodes with possible involvement and all such lymph nodes were submitted for microscopic examination. Gross pathological examination of specimens is performed by trained gross room assistants. During the study period, the same group of assistants handled all the cases. In our practice, we do not routinely use fat-resolving agents for lymph node dissection. Microscopic examination of all colorectal resection specimens was performed by specialized gastrointestinal pathologists at our institution. The differentiation of positive lymph nodes from tumour deposits followed current recommendations.[21] The surgical pathology report was reviewed for details including total specimen length, lymph nodes retrieved, location of tumour from the proximal edge of the specimen and seventh edition AJCC tumour stage.
Univariable analyses using analysis of variance (ANOVA), chi-square and non-parametric alternatives were used to compare characteristics and outcomes between O-RC, L-RC and R-RC cohorts. Tukey’s range test was used for multiple comparisons between the techniques. There were two primary endpoints for this study: total LN yield and the LN to length of surgical specimen (LN-LSS) ratio.
Multivariable modeling using a mixed effects model was used to predict LN yield and LN-LSS ratio. Model selection began with stepwise selection of relevant clinical, demographic and operative variables using SAS version 9.4. Several variables posed a high likelihood of collinearity including tumour distance from the proximal resection margin, extended versus standard RC, ligated vessels and specimen length. Correlation matrices were used to choose between variables that could lead to collinearity, and to exclude potentially intermediate variables, whose inclusion would lead to over-adjustment. The final model consisted of both those variables that had been selected by stepwise regression and those determined to be relevant by a priori knowledge. Surgeons and pathologists were considered random effects in order to control for differences in technique and skill. Variance inflation factor and residual analyses were used to verify the robustness of the model. Analyses were conducted on an “intent-to-treat” basis with a p value of less than 0.05 considered statistically significant. A sensitivity analysis excluding Stage IV disease was performed. An “as-treated” analysis was also conducted in which laparoscopic and robotic cases that were converted to open were re-categorized as open cases.
Results
A total of 181 O-RC, 163 L-RC and 119 R-RC cases met the inclusion criteria. Demographics and tumour characteristics are listed in Table 1. Patients in these cohorts differed in terms of sex and AJCC stage, with patients in the open group more likely to be female and to have Stage IV disease compared to L-RC and R-RC patients. MMR status by IHC was determined in 294 patients. The proportion of patients with MMR-deficiency was not significantly different amongst the study groups.
Table 1.
Demographic and Clinical Characteristics by Surgical Approach
| O-RC (181) |
L-RC (163) |
R-RC (119) |
p | ||
|---|---|---|---|---|---|
| Age y, median (IQR)* | 64 (53–75) | 64(54–75) | 68 (58–77) | 0.13 | |
| Male n (%) | 72 (40) | 83 (51) | 64 (54) | 0.03 | |
| BMI median (IQR)* | 27 (24–33) | 29 (25–32) | 28 (24–32) | 0.16 | |
| Race n (%) | 0.86 | ||||
| Caucasian | 147 (81) | 140 (86) | 97 (82) | ||
| TNM Stage n (%) | <0.01 | ||||
| I | 23 (13) | 36 (22) | 27 (23) | ||
| II | 38 (21) | 62 (38) | 46 (39) | ||
| III | 33 (18) | 55 (34) | 38 (32) | ||
| IV | 87 (48) | 10 (6) | 8 (7) | ||
| Abnormal MMR Expression n (%)** | 36 (32) | 38 (40) | 28 (33) | 0.46 | |
Kruskal-Wallis test
n= 294
There were significant differences in operative details between groups (Table 2). Patients undergoing O-RC were more likely to have had concurrent major procedures (41% versus 12% in L-RC, and 5% in R-RC), most of them liver resections. Compared to R-RC, patients undergoing L-RC were more likely to have conversions to open, and accordingly, to have ligation of the vascular pedicle done in an extracorporeal fashion after termination of laparoscopy. Robotic RC patients had almost exclusively intracorporeal vascular pedicle ligations and were the most likely to have undergone preoperative tattooing of the tumour.
Table 2.
Operative Details by Surgical Approach
| O-RC (181) | L-RC (163) | R-RC (119) |
p | ||
|---|---|---|---|---|---|
| Operative Time min, median (IQR)* | 167 (113–245) | 148 (116–186) | 156 (131–182) | 0.03 | |
| Tattoo n (%) | 49 (27) | 50 (31) | 57 (48) | <0.01 | |
| Extended RC n (%) | 36 (20) | 24 (15) | 30 (25) | 0.09 | |
| Intracorporeal Vessel Ligation n (%) | 0 | 117 (72)+ | 114 (96)++ | <0.01 | |
| Concurrent Major Surgery n (%) | 75 (41) | 20 (12) | 6 (5) | <0.01 | |
| Conversion to Open n (%) | ----- | 33 (20) | 3 (3) | <0.01 | |
| Vessels Ligated n (%) | 0.04 | ||||
| Ileocolic/RC Only | 49 (27) | 56 (34) | 23 (19) | ||
| Ileocolic/RC /Right Branch Of Middle Colic | 98 (54) | 87 (53) | 71 (60) | ||
| Ileocolic/RC/ Right and Left Branches Of Middle Colic | 34 (19) | 20 (12) | 25 (21) | ||
Kruskal-Wallis test
Of 46 extracorporeal ligations, 31 were in the setting of conversion to open.
Of 5 extracorporeal ligations, 3 were in the setting of conversion to open.
The colectomies were performed by six colorectal surgeons. The frequencies of open, laparoscopic and robotic cases performed by each surgeon are listed in Table 3. Five of the surgeons performed at least one case with each of the three approaches. Two of the surgeons accounted for nearly 90% of robotic colectomies performed. The rates of conversion to open surgery ranged from 0 to 47% among the six surgeons.
Table 3.
Operative Approaches and Rates of Conversion to Open Surgery for the Six Surgeons
| Surgeon ID | O-RC (181)* |
L-RC (163)* |
R-RC (119)* |
Conversion To Open** |
|---|---|---|---|---|
| 1 | 15 (8) | 9 (6) | 55 (46) | 2 (3) |
| 2 | 32 (18) | 29 (18) | 8 (7) | 5 (14) |
| 3 | 27 (15) | 37 (23) | 5 (4) | 3 (7) |
| 4 | 55 (30) | 32 (20) | 4 (3) | 17 (47) |
| 5 | 32 (18) | 22 (13) | 47 (39) | 0 (0) |
| 6 | 20 (11) | 34 (21) | 0 (0) | 9 (26) |
n (% of all open, laparoscopic or robotic cases)
n (% of surgeon’s laparoscopic or robotic cases)
Postoperative complications are listed in Table 4. Overall, 106 patients (23%) experienced a postoperative complication, with Clavien-Dindo grade 3 or higher-grade complications occurring in 34 (7%) patients. The rate of superficial and deep surgical-site infections was 8%, and the rate was significantly higher for open surgery patients than for laparoscopic or robotic surgery patients (p < 0.01). The overall rate of anastomotic leaks and intra-abdominal abscesses was 6%, and again, the rate was significantly higher for open surgery patients than for laparoscopic or robotic surgery patients (p < 0.01).
Table 4.
Postoperative Complications by Surgical Approach
| O-RC (181) |
L-RC (163) |
R-RC (119) |
p | |
|---|---|---|---|---|
| Any Complication n (%) | 68 (38) | 22 (13) | 16 (14) | < 0.01 |
| CD* Grade ≥ 3 complications n (%) | 27 (15) | 4 (3) | 3 (3) | <0.01 |
| Surgical Site Infections (SSI) | 46 (25) | 12 (7) | 7 (6) | <0.01 |
| Superficial and Deep SSI n (%) | 27 (15) | 8 (5) | 4 (3) | <0.01 |
| Organ Space SSI n (%) | 19 (10) | 4 (2) | 3 (3) | <0.01 |
| Ileus/Small Bowel Obstruction n (%) | 5(3) | 5(3) | 1(1) | 0.44 |
| Mortality n (%) | 2 (1) | 1(1) | 0 | 0.51 |
Clavien-Dindo classification
Pathological outcomes are shown in Table 5. The LN yield was highest among patients undergoing R-RC with a mean of 34, compared with the lowest LN yield in patients undergoing O-RC, in which a mean of 28 LN were recovered. Univariable analysis showed significant differences in LN yield between the cohorts (p < 0.01). Tukey’s range test was used for multiple comparisons and showed that R-RC resulted in a significantly greater LN yield compared to L-RC and O-RC (both p < 0.01). Robotic RC resulted in the highest LN-LSS ratio, approaching 1. Laparoscopic RC cases produced a mean ratio of 0.91, and O-RC had the lowest ratios, with a mean of 0.83. These differences were significant on univariable analysis, but in multiple comparisons analysis, only the R-RC versus O-RC comparison was statistically significant (p < 0.01).
Table 5.
Univariable Analyses of Pathological Outcomes by Surgical Approach
| O-RC (181) |
L-RC (163) |
R-RC (119) |
p | |
|---|---|---|---|---|
| LN Yield n, mean(SD) | 28 (12) | 29 (14) | 34 (17) | <0.01 |
| Length of Surgical Specimen cm, median(IQR)* | 36 (27–45) | 33 (27–40) | 35 (29–41) | 0.06 |
| LN-LSS Ratio mean(SD) | 0.83 (0.4) | 0.91 (0.4) | 1.0 (0.5) | <0.01 |
Kruskal-Wallis Test
In multivariable analysis, R-RC was associated with higher LN yield, with approximately 4 more harvested nodes compared to O-RC and L-RC (Table 6). These findings were even more pronounced in sensitivity analyses excluding Stage IV disease. Location of the tumour (further distance from the proximal margin) and increased tumor size were also associated with increased LN yield, whereas older age was associated with decreased LN yield. A preoperative tattoo mark was associated with a higher LN yield and concurrent surgical procedures were associated with lower LN yield, though these findings were not significant after exclusion of stage IV cancers.
Table 6.
Linear Mixed Model Predicting LN Yield with Robotic RC as the reference group
| All Stages | Stage 4 Excluded | |||
|---|---|---|---|---|
| Estimate of Effect (95% CI)* |
p | Estimate of Effect (95% CI)* |
p | |
| Open | − 4.3 (−8.1, −0.7) | 0.02 | −5.5 (−9.6, −1.5) | 0.01 |
| Laparoscopic | − 4.3 (−7.8, −0.9) | 0.02 | −4.9 (−8.4, −1.4) | <0.01 |
| Age (years) | −0.2 (−0.2, −0.1) | <0.01 | −0.1 (−0.02, −0.015) | 0.02 |
| Female | −1.0 (−3.4, 1.4) | 0.45 | −1.0 (−3.9, 2.0) | 0.53 |
| Caucasian Race | −0.3(−3.4, 2.9) | 0.87 | −0.4 (−4.3, 3.4) | 0.86 |
| Stage | 0.9 (−0.5, 2.3) | 0.23 | 1.2 (−8.4, 3.2) | 0.26 |
| Size (cm) | 0.5 (0.1, 1.0) | 0.02 | 0.8 (0.2, 1.3) | 0.01 |
| Distance of tumour from proximal margin (cm) | 0.16 (0.1, 0.3) | <0.01 | 0.1 (0, 0.2) | 0.046 |
| Concurrent Surgery | −3.5 (−6.3, −0.4) | 0.03 | −3.7 (−7.5, 0.3) | 0.07 |
| Tattoo | 2.8 (0.4, 5.6) | 0.047 | 2.4 (−0.5, 5.7) | 0.14 |
negative estimates indicate a decrease in LN yield
Compared to R-RC, O-RC was associated with a significantly lower LN-LSS ratio in multivariable analyses, while L-RC showed a lower estimate, but this difference was not significant (Table 7). A preoperative tattoo mark increased the ratio by 0.09. Older age, increased tumour distance from the proximal resection margin and higher BMI were associated with lower LN-LSS ratios.
Table 7.
Linear Mixed Model Predicting LN-LSS Ratio with Robotic RC as the reference group
| All Stages | Stage 4 Excluded | |||
|---|---|---|---|---|
| Estimate of Effect (95% CI)* |
p | Estimate of Effect (95% CI)* |
p | |
| Open | −0.17 (−0.3, −0.1) | <0.01 | −0.24 (−0.4, −0.1) | <0.01 |
| Laparoscopic | −0.05 (−0.1, 0.1) | 0.37 | −0.09 (−0.2, 0.04) | 0.13 |
| Age (years) | −0.01 (−0.01, 0) | <0.01 | −0.01 (−0.01, 0) | <0.01 |
| Female | −0.02 (−0.1, 0.1) | 0.68 | −0.01 (−0.1, 0.1) | 0.80 |
| Caucasian Race | −0.04 (−0.1, 0.1) | 0.46 | −0.07 (−0.2, 0.03) | 0.20 |
| BMI | −0.01 (−0.01, 0) | 0.03 | −0.01 (−0.01, 0) | 0.18 |
| Stage | 0.03 (−0.01, 0.08) | 0.11 | 0.04 (−0.02, 0.1) | 0.24 |
| Size (cm) | 0.01 (0, 0.02) | 0.16 | 0.01 (0, 0.03) | 0.08 |
| Distance of tumour from proximal margin (cm) | −0.01 (−0.01, 0) | <0.01 | −0.01 (−0.01, 0) | <0.01 |
| Conversion | −0.14 (−0.3, 0.01) | 0.09 | −0.13 (−0.3, 0) | 0.11 |
| Tattoo | 0.09 (0.01, 0.2) | 0.04 | 0.08 (0, 0.2) | 0.10 |
negative estimates indicate a decrease in LN-LSS ratio
An additional analysis was performed with O-RC as the reference group. In this analysis, L-RC and O-RC were associated with similar LN yields (p =0.99), while both L-RC and R-RC cases were associated with significantly increased LN-LSS ratios (p= 0.03 and < 0.01 for L-RC and R-RC, respectively). For both outcomes, we performed sensitivity analyses in which minimally invasive cases that were converted to open were reclassified as O-RC. The results of these sensitivity analyses did not alter the findings of the intent-to-treat analyses.
Discussion and Conclusions
The findings of this study indicate that robotic colectomy for colon cancer is associated with higher LN yield compared to both open and laparoscopic colectomy. In addition, we found that minimally invasive colectomy is associated with higher LN-LSS ratios, with the highest ratio seen in R-RC cases.
Our study confirms previous observations from our own institution; preoperative tattooing is associated with a higher lymph node yield, but MMR status is not associated with lymph node yield. [15, 22] Increasing age was associated with a decrease in both LN yield and LN-LSS ratio, while increasing tumour size was associated with an increase in LN yield only. The significance of these findings is unclear given the small magnitude of the associations between these factors and the outcomes of interest.
Lymph node yield can be increased either by harvesting more paracolic nodes through a longer surgical specimen, or by increasing the uptake of intermediate and central nodes through a higher ligation of the vascular pedicle, or both. Therefore, LN yield alone cannot be considered a surrogate of complete mesocolic excision (CME) with central vascular ligation (CVL). By dividing the number of lymph nodes retrieved by the length of the surgical specimen, the LN-LSS ratio may provide an indirect indication of the completeness of the mesocolic excision. In the case of a longer specimen without a higher vascular ligation, we would expect little change in the LN-LSS ratio since the specimen length would be increasing concurrently with LN yield. However, a resection with a higher ligation of the vascular pedicle would be expected to increase this ratio, assuming an equivalent length of resection.
Few studies to date have reported LN yield after R-RC. A recent systematic review of the six largest studies comparing R-RC and L-RC included only two studies with pathological data, and in only one could the LN yield after RC be readily abstracted.[23] A prospective trial from Korea comparing 35 patients having R-RC with the same number of patients having L-RC, reported equivalent LN yields - 29.9 and 30.8, respectively.[24]. As the length of the surgical specimen was longer in the R-RC group, the LN-LSS ratio would likely have been lower in the R-RC group as well. This discrepancy with our study cannot be simply attributed to differences in patient population, because race and BMI have not been previously shown to be independently associated with LN yield. It is possible that the differences may be attributable to differences in surgical technique, both in R-RC and L-RC. For example, in the Korean study, the mesenteric dissection was performed from lateral to medial, while in our center, the operation typically starts with central vascular control followed by a medial to lateral approach. However, the impact of this surgical technique on lymph node yield remains speculative.
While the absolute number of lymph nodes may be associated with a survival advantage, recent evidence suggests that the completeness of the mesocolic excision also has prognostic implications.[25, 26] A complete mesocolic excision has been associated with a larger lymph node yield by removing the centrally located nodes close to the named vascular pedicles. Institutional case series, and more recently a population-based study, have found an association between complete CME with CVL and improved survival in patients with colon cancer. [27–29] In the Danish study, this survival benefit was associated with higher rates of intra-abdominal organ injuries and non-surgical complications compared to conventional colon resections.[30] In our study, the overall rate of complications was comparable to those in the two arms of the Danish study and no intra-abdominal organ injuries or superior mesenteric vein injuries occurred.
An important limitation of this study is its retrospective design. Measuring the length of the vascular pedicle at the time of surgery could have provided a separate method to assess central vascular control. It is likely that only examination of the surgical specimen could establish which nodal groups (paracolic, intermediate, apical) were excised. In addition, multiple surgeons, pathologists and pathology assistants were involved in this study. As in all studies of this nature, such confounders are difficult to eliminate. However, by using a mixed-effects model, with surgeon and pathologist as random variables, we accounted for the potential variability introduced by differences in technical proficiency.
In conclusion, R-RC is associated with a higher LN yield compared to O-RC and L-RC, and a higher LN-LSS ratio compared to O-RC. Our study suggests that the improved visualization and dexterity provided by the robotic platform may facilitate the performance of a CME and CVL. These findings should be validated in a prospective study with confirmation of the height of the vascular pedicle ligation.
What does this paper add to the literature?
This is a retrospective study of 463 patients undergoing right colectomy for colon cancer. We compared the lymph node yield and lymph node to length of surgical specimen ratio (LN-LSS) after open (O-RC), laparoscopic (L-RC) and robotic (R-RC) right colectomy. We found that R-RC may facilitate a better mesocolic excision.
Acknowledgments
The authors would like to acknowledge Dr. Patricio Lynn for his assistance in data collection.
This study was supported in part by NCI grant P30 CA008748.
Footnotes
None of the authors had a conflict of interest.
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