Oncological Implications of Lymph Nodes Retrieval and Perineural Invasion in Colorectal Cancer: Outcomes from a Referral Center

Oncological Implications of Lymph Nodes Retrieval and Perineural Invasion in Colorectal Cancer: Outcomes from a Referral Center

INTRODUCTION
Colorectal cancer (CRC) is a common disease that has high morbidity and mortality rates. It is estimated that about 140,250 new cases of CRC are diagnosed annually in the United States and approximately 50,630 people die every year due to this condition1. CRC mortality has been progressively reduced since 1990 at a rate of about 3% per year2. In Mexico, CRC is the third most frequent type of cancer and is the sixth leading cause of cancer death3. Surgical resection is the only curative treatment modality for localized colon cancer. Regional lymphadenectomy, besides, being a quality indicator in CRC surgery, provides prognostic information, and guides post- operative management, such as the administration of chemotherapy. There is a direct correlation between the number of lymph nodes (LN) examined per patient after surgical resection and survival4. However, the concept of such sequential progression or meta- static cascade, in which the primary tumor seeds LN metastases that, in turn, seed distant metastases, provides a simplistic theory. Some studies have shown that the removal of LN does not always improve patient survival5,6. Naxerova et al. analyzed variants in hypermutable DNA regions, finding that in 65% of the cases, lymphatic and distant metastases arose from independent subclones in the primary tumor, whereas in 35% of cases they shared a common sub- clonal origin5.

The current consensus in the world literature is that at least 12 LN must be examined for adequate stag- ing. However, recommendations range from 6 to 18 LN7-11. The American Society of Clinical Oncology recommends the use of adjuvant chemotherapy for patients suffering from node-negative colon cancer if there are < 12 LN in the surgical specimen12. In a meta-analysis of 17 studies, the number of LN examined per patient correlated significantly with over- all survival and 5-year recurrence rates in patients with Stage II and III colon cancer4,13-17. The more obvious explanation is that the greater the removal of LN, the greater the accuracy of the staging classification. However, the strong association between total LN count and survival is not fully explained by an improved staging classification18-20. In this way, the LN number has been proposed as a quality indica- tor for CRC surgery21. The differences between patients with CRC in terms of the number of LN collected are influenced by multiple factors such as size, location, degree of differentiation, tumor biology, obesity, surgical approach, surgeon’s experience, histopathological analysis, and neoadjuvant treatment22-27.

Due to the aforementioned controversies, new parameters have been described to improve the prediction of oncological outcomes. One of these parameters is the LN ratio (LNR), which is calculated by dividing the number of positive LN by the total number of LN examined. There is no consensus about the LNR cutoff value, but most coincide in a value of 0.2528-30.

The objectives of our study were to analyze the impact of the number of LN on recurrence and survival in patients who underwent a curative CRC resection and to examine factors that influence LN retrieval. In addition, to examine the role of LNR and perineural invasion (PNI) in predicting prognosis after curative resection of CRC.

MATERIALS AND METHODS
We included all patients who had curative resection for CRC (Stages I, II, and III) at a referral center in Mexico City between January 2000 and December 2016. The diagnosis of CRC was made by histopathological examination. We excluded patients with loss to follow-up (n = 4), incomplete pathology report (n = 5), operative mortality (n = 16), Stage IV cancers (n = 89), and those requiring only a derivative stoma due to obstruction (n = 5). We obtained data from a prospective database and veri- fied the data with hospital charts. Two groups according to the number of LN retrieved were initially analyzed: Group 1 (≥ 12 LN) and Group 2 (< 12 LN). Similarly, we analyzed several factors that influence the number of LN retrieved: gender, age, localization, body mass index (BMI), laparoscopic surgery, neoadjuvant therapy, and the tumor’s histology. Different cutoff values for the total number of LN (6, 9, 12, 15, and 18) were used to analyze if there were differences in recurrence or mortality. LNR was calculated in patients with Stage III tumors, and we took a cutoff value of 0.25 according to the revised bibliography31. We also analyzed surgeries performed for each year and classified them into two groups: those performed before 2009 and those after this year, because since that date, the synoptic pathology report was introduced in our hospital. Board-certified pathologists performed histopathological assessments of hematoxylin and eosin stained slides. PNI was defined as identification of tumor cells spreading to the space surrounding a nerve. The study was approved by the institutional ethics review board (SCI-2206-17/17-1).

Descriptive analysis of the variables registered was conducted using measures of central tendency and spread according to whether they were continuous or categorical variables. Chi-square or Fisher’s exact test was used for the statistical contrast of the categorical variables according to whether they were variables with normal distribution or not. Odds ratio with 95% confidence interval was calculated to corroborate the statistical power in the univariate analysis. The influence of variable factors on disease-free survival was estimated using the Kaplan–Meier method. ANOVA was used to determine whether the means of the categorical variables between the groups were the same. We also utilized a Cox proportional hazard model to analyze factors associated with disease-free survival for multivariate analyses. The association between LNR and recurrence was assessed by the receiver operating characteristic curve. The corresponding area under the curve was also calculated. A difference with p < 0.05 was considered statistically significant. Statistical analyses were performed using SPSS version 20.0 software (SPSS Inc., Chicago, IL, USA).

RESULTS
Between 2000 and 2016, 424 patients underwent CRC surgery in a referral center in Mexico City. A total of 305 patients were included in the study, 42 (13.8%) patients in Stage I, 139 (45.6%) in Stage II, and 124 (40.6%) patients in Stage III. The male:female ratio was 1.1. The mean age was 62.6 ± 14.4 years (range, 19-92). The mean of BMI was 25.5 ± 4.7 (range, 14-44). Tumor localization sites were 106 (34.7%) in the cecum and ascending colon, 16 (5.2%) in the transverse colon, 18 (5.9%) in the descending colon, 71 (23.2%) in the sigmoid colon, and 90 (29.5%) in the rectum. Four (1.3%) patients with synchronous tumor were detected. Surgeries were performed laparoscopically in 163 patients (53.4%), with a conversion rate of 11.1%.

The surgical procedures were 111 right colectomies, 2 transversectomies, 24 left colectomies, 43 sigmoid resections, 67 low anterior resections, 19 abdominoperineal resections, 15 total colectomies, 7 pelvic exenteration, and 6 proctocolectomies.

The mean LN harvest was 17.25 with a range from 0 to 63. In 233 (76.4%) patients, 12 or more LN were obtained in the surgical specimen. The average number of LN in Group1(≥12LN)andGroup2(<12 LN) was 20.89 ± 8.98 and 5.44 ± 4.33, respectively (Table 1).

We identified that, from 2000 to 2016, the LN harvest increased over time. We also analyzed surgeries in two groups: those performed before 2009 and those after this year. In the first group (2000-2008), 110 surgeries were performed, of which 68 (61.8%) had ≥ 12 LN; of 195 surgeries in the second group (2009-2016), 165 (84.6%) had ≥ 12 LN (odds ratio [OR] 3.397; 95% confidence interval [CI]: 1.966- 5.871; p ≤ 0.0001). The differences of LN retrieval over time are shown in figure 1.

The mean follow-up time was 47.8 months (range from 15 days to 200 months). Overall, the recurrence rate was 21.6% (66 patients), with an average recurrence time of 24.6 months (range from 2 to 132). The recurrence rates in Group 1 (≥ 12 LN) and Group 2 (< 12 LN) were 20.2% and 26.4% (p = 0.16), respectively. Overall, 5-year survival was 83.6%. The 5-year survival rates in Group 1 and Group 2 were 90.1% and 87.3% (p = 0.74), respectively (Fig. 2). When analyzing overall survival by stages, no significant differences were found between LN harvest ≥ 12 and < 12: in Stage I cancers, 93.8 versus 90% (p = 0.46); in Stage II, 91.7 versus 76.7% (p = 0.10); and in Stage III, 83.9 versus 87.1 (p = 0.36). The recurrence and mortality rates were assessed according to clinical stages, and we found that Stage III cancers had higher recurrence rates compared with Stages I and II (OR 2.05, 95% CI: 1.18-3.57; p = 0.007) (Table 2).

According to the number of LN, we found higher local and distant recurrence rates in patients with < 6 and 9 LN compared to those with ≥ 12 LN, 36.4% and 34.1% versus 20.2% (p = 0.03), respectively. Overall, recurrence rates according to the number of LN were as follows: 36.4% (< 6 LN) versus 19.9% (≥ 6 LN); 34.1% (< 9 LN) versus 19.5% (≥ 9 LN); 26.4% (< 12 LN) versus 20.2% (≥ 12 LN); 25.4% (< 15 LN) versus 19% (≥ 15 LN); and 22.9% (< 18 LN) versus 20% (≥ 18 LN) (p = 0.0001). A number of LN retrieved > 12 did not show additional benefits on recurrence or survival (Table 2).

The LNR was calculated in Stage III tumors. In 26 patients (9.9%), the LNR was higher than 0.25. Over- all, survival rates in patients with an LNR < 0.25 ver- sus those with an LNR ≥ 0.25 were 88.1% versus 73.1% (p = 0.009), respectively. Patients with an LNR ≥ 0.25 had higher recurrence (OR 3.57, 95% CI: 1.56- 8.16; p = 0.012) and mortality rates (OR 2.94, 95% CI: 1.14-7.57; p = 0.029) (Table 2). The overall dis- ease-free survival was 42 months in patients with an LNR < 0.25, and it was 18 months in patients with an LNR ≥ 0.25 (p < 0.001) (Figs. 3 and 4).

Lymphovascular invasion (LVI) and PNI were present in 61 (23.7%) and 34 (13.2%) cases, respectively. We did not find statistically significant differences by comparing LVI with recurrence (OR 1.02, 95% CI: 0.51-2.03; p = 0.54) and mortality (OR 2.05, 95% CI: 0.96-4.35; p = 0.05). However, we found higher recurrence (OR 2.79, 95% CI: 1.33-5.86; p = 0.007) and mortality (OR 2.87, 95% CI: 1.22-6.73; p = 0.018) when PNI was present (Table 2). The overall disease- free survival was 21.4 months for patients with PNI- positive tumors, and it was 44 months for patients with PNI-negative tumors (p = 0.001) (Fig. 5). In a multivariate Cox regression analysis, PNI-negative tumors were an independent prognostic factor for dis- ease-free survival (p = 0.011, hazard ratio [HR] = 2.78, 95% CI = 1.26-6.16).

The factors associated with an increased number of LN retrieved were tumors located in the colon, laparoscopic surgeries, and surgeries performed after the introduction of the synoptic pathology report (Table 3).

DISCUSSION
There is currently sufficient evidence to demonstrate that LN involvement is a prognostic factor and quality indicator for CRC surgery4. However, the exact number of LN that should be examined has not yet been well determined. In addition, in the literature, there is much controversy on determining a minimum number in which there would be no substaging risk. Hernanz et al. showed that if 6 LN were examined the probability to find at least, a positive LN was 95 % and that this probability increased to 99% if 10 LN were examined. Therefore, the authors concluded that 6 LN provided an accurate assessment of the presence of nodal metastasis32. In our series, LN harvest of < 6 or 9 had a significant impact on recurrence and mortality rates. Goldstein et al. and Maurel et al. showed that the probability of correctly classifying a colorectal tumor as node-positive increased as the number of examined LN. They also reported that this increase had a plateau. In their two series of patients, this plateau was reached when 17 LN in one series and 16 in the other had been examined33,34. We show in our study that an LN count of 12, 15, or 18 had no additional benefit on predicting recurrence or mortality and that a plateau is observed from 12 LN. This plateau is not observed when the nodal harvest is < 6 or 9 LN. Cianchi et al. found that the 5-year survival rate of Stage II patients with 8 or fewer LN examined was similar to that of Stage III patients. Their results suggested that examining a minimum of 9 LN per surgical specimen may be sufficient for reliable staging of LN-negative tumors11. Swanson et al. classified patients with T3N0 colon cancer into three groups according to the number of LN examined and found that a minimum of 13 LN should be examined to label the cancer as node negative35. Baxter et al. found that in the United States, only 37% of patients received adequate LN evaluation (i.e., at least 12 LN examined), and the median number of LN for all patients was 936. In our series, more than 75% of patients had 12 or more LN examined in the surgical specimen. We consider that the quality of our surgeries was high in relation to the number of retrieved LN and that the low proportion of pa- tients with < 12 LN was the reason why we did not obtain statistical significance in the multivariate analysis.

More recently, Mason et al. established that only 46% of high-performance hospitals in the United States adhere to an LN collection ≥ 1237. On the other hand, when taking different cutoff values from the LN, we found that a harvest < 6 or 9 had a significant impact on overall recurrence rates. In a study, Zhang et al. showed that LN count did not significantly affect survival, whereas LNR was found to be significant for predicting mortality and recurrence at Stage III29. Similarly, Tsikitis et al. analyzed a series of 329 patients in Stage III where they did not find a significant association between ≥ 12 and < 12 nodes on survival; however, they found a positive correlation between the number of positive nodes and survival22.

Variations in the ability of the pathologists to search for LN and the different statistical methods used in the published series are probably the main factors that explain the considerable variation. The number of nodes harvested depends on several factors such as sex, location of the tumor, depth of lesion, extent of lymphadenectomy, and the ability of the surgeon and pathologist to identify and collect LN. Different studies have reported that LN metastases in CRC are often found in small LN (< 5 mm in diameter)30,38,39. In our study, we found that tumors located in the colon, the laparoscopic approach, and surgeries per- formed after the implementation of a multidisciplinary team management were determinants to obtain a greater number of LN.

Some authors have found that the use of a synoptic pathology report improved the mean number of LN harvested, and more frequently, the minimum number of 12 LN was achieved40. At our institution, the proportion of specimens with more than 12 LN increased after the adoption of a synoptic pathology reporting for CRC in 2009.

On the other hand, there is enough evidence that the laparoscopic approach has the same oncological out- comes compared to the open approach41-44. Most of the literature refers to the existence of a larger LN harvest in the open approach45. As such, we believe that these results are because, since 2009, only board-certified colorectal surgeons perform all laparoscopic CRC surgeries at our hospital. We obtained a trend toward statistical significance of greater LN retrieval in rectal cancer patients who did not receive neoadjuvant therapy. Abdel-Misih et al. demonstrated in their study that patients receiving neoadjuvant chemoradiation had a lower number of LN collected with a mean of 15 compared to 17 and 18 for non-neoadjuvant and neoadjuvant chemotherapy, respectively (p ≤ 0.0001)46. We believe that we did not obtain statistical significance due to our small sample size.

LVI and PNI have proven to be independent prognostic factors of recurrence and mortality in CRC. LVI refers to the involvement of small lymphatic or blood (typically venous) vessels by the tumor, and PNI refers to the growth of tumor in, around, and through nerves and nerve sheaths. It is believed that both variables denote an aggressive phenotype, increased node involvement, poor tumor differentiation, greater depth of tumor invasion, and, therefore, higher rates of recurrence and mortality. Al-Sukhni et al. identified that specific PNI was independently associated with reduced survival (HR 3.55, 95% CI: 1.78- 7.09)47. Similar to our results, other authors have found that PNI is an independent prognostic factor affecting disease-free and overall survival in patients with colon cancer48,49.

The LNR has been proposed as an easy way to im- prove the predictive value of metastatic involvement of LNs, which for some authors would be higher than the number of positive LNs50,51. In different series, LNR has shown to be a relevant prognostic factor in patients with collected positive LN and poorly staged patients initially classified as Stages I and II, espe- cially if the LN count is higher than or equal to 12. The strong interaction between the number of LN examined, the number of metastatic LN and the LNR does not allow a categorical conclusion of which is the most prominent prognostic factor. In our series, an LNR higher than 0.25 was an independent predictor of recurrence and survival in patients with Stage III tumors.

In conclusion, an LN harvest lower than 10 increased local and distant recurrence rates. The LNR is an independent prognostic factor for recurrence and over- all survival in Stage III tumors. In our study, we demonstrated that a greater LN retrieval was associated with tumors located in the colon, a laparoscopic approach, and the absence of neoadjuvant treatment. PNI was the only significant independent prognostic factor affecting disease-free survival.

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