Evaluation of lymph node adequacy in patients with colorectal cancer: Results from a referral center in Iran

Colorectal cancer is one of the leading causes of cancer-related mortality worldwide. Additionally, its incidence rate in Iran has been increasing over the last 25 years. Based on the cancer registry data reported in 2014, colorectal cancer is the third most common cancer following breast and stomach cancers in Iranian people and has an annual incidence rate of more than 7100 cases. In the same year, the age-standardized incidence rate of this disease per 100,000 population was found to be 15.18% and 11.12% for men and women, respectively^[1].

It is well known that the presence of lymph node metastasis is one of the most important and effective prognostic factors for long-term survival of patients with colorectal cancer^[2].

Therefore, thorough pathologic examination of an adequate number of lymph nodes is essential for accurate staging of this disease as well as for choosing the best adjuvant treatment. Currently, adequate lymphadenectomy is defined as the presence of at least 12 lymph nodes in the surgical specimen. In this regard, previous studies have shown that a higher number of harvested lymph nodes is associated with increased survival rate^[3].

Achieving the standard number of 12 resected lymph nodes, however, is not always possible, and many studies have previously demonstrated that inadequate retrievals are still performed in a considerable number of patients with this disease^[4].

Several factors affect the count and the quality of harvested lymph nodes during the surgery of colon cancer, including the surgeon’s expertise, extent of surgical resection, and experience of the pathology department and the pathologist, as well as some patient-related factors such as obesity, age, gender, and site of tumor^{[5, 6]}.

An inadequate number of resected lymph nodes may result in a worse prognosis. Accordingly, patients with fewer examined lymph nodes might be erroneously down-staged and as a result, they might not receive the necessary adjuvant treatments^[7].

This study aimed to assess the adequacy of lymph node harvest in patients with colorectal cancer treated in a referral public hospital.

This observational cross-sectional study included 584 patients with colorectal adenocarcinoma who had undergone surgery (open or laparotomy surgery) between 2012 and 2017. Patients with incomplete records and missing necessary data (related to the objectives of our study) were excluded from the study. The surgical team working on the patients included in the study were all colorectal surgeons specializing in colorectal cancer.

Relevant demographic, pathological, and surgical data were extracted from the patients’ medical records and then inserted into a checklist consisting of several items, including age, gender, tumor site, pathologic stage, grade, number of dissected lymph nodes, tumor size, and number of the involved lymph nodes.

We obtained 584 records of the patients included in this study (350 men and 234 women) who had undergone surgery for colorectal cancer from 2012 to 2017. Among them, 257 (40%) patients had elective surgery, and 327 (56%) had emergency surgery. The mean age of the patients was 59.4 (±13.3) years old, and their ages ranged from 23 to 87 years old.

In the current study, the majority of the cases (50%) had T3 disease followed by T4 (34.1%), T2 (12.5%), and T1 (1.4%) tumor stages. Staging was recorded using TNM scoring system (Tumor size, Lymph Nodes affected, Metastases) based on the 7^th edition of American Joint Committee on Cancer staging system (AJCC 7th Edition). The demographic and clinical characteristics of the studied patients are shown in Table 1.

The data obtained showed that in 336 (57.5%) patients, fewer than 12 lymph nodes had been assessed. Thereafter, the mean and median of the number of evaluated lymph nodes were calculated as 10.7 (±5.6) and 10, respectively.

Among various studied parameters, age and tumor site were found to be associated with the number of the lymph nodes retrieved. In this study, we found that the odds of having fewer than optimal assessed lymph nodes were higher in the patients aged 60 years old and above compared to the patients aged 40 years old and younger (OR = 2.42; 95% CI = 1.29–4.53).

Age can be an important factor to consider in estimating the survival rate of patients. Among the patients participation in the study, it was found that the older the patient, the lower the survival rate. Moreover, the patients over the age of 50 years old died, and their survival rates were lower than those of other younger patients. Therefore, age can be considered to be a predictor for number of lymph nodes retrieved, and a statistical significance also was found for survival difference for younger and older patients.

In addition, our results show that patients with tumors located in descending colon or rectum had higher odds of having a lower number of the evaluated lymph nodes compared to the patients with tumors located in ascending or transverse colon (OR = 2.47; 95% CI 1.49 – 4.09 and OR = 2.37; 95% CI 1.42 – 3.94, respectively). It should be noted that all the patients with rectal involvement enrolled in this study were treated according to the NCCN (National Comprehensive Cancer Network) guidelines for neoadjuvant therapy. None of the patients received neoadjuvant-based treatments except those with rectal involvement.

We observed no relationship between other variables such as gender, tumor size, T-stage, and grade and number of dissected lymph nodes (Table 2).

After an average follow-up of 60 months (ranging from 36 to 96 months), 369 (63%) patients with colorectal cancer were still alive. Median survival time for all cases (584) was 49 months. Fewer than 12 lymph nodes had been assessed in 57.5% of of the patients in the study, and their median survival time was 48 months. Additionally, in 39.4% of the patients, the number of the lymph nodes evaluated was ≥12, and median survival time was 54 months (Table 3). As shown in the table, survival was also assessed by considering neoadjuvant treatments. The study showed that neoadjuvant theoretical complementary therapies can affect patient survival.

Adequate lymphadenectomy in colorectal cancer is essential to define the stage as well to plan the adjuvant therapy, especially for cases at stage III^[8]. Furthermore, several studies have demonstrated that adequate lymph node retrieval might be associated with a reduced risk of death and an improved survival rate^{[3, 9]}.

The results of our study show that in more than half of the patients (57.5%), the number of the evaluated lymph nodes was below the current standard number of 12, with a mean and median of 10.7 (± 5.6) and 10 in the examined lymph nodes, respectively. Age and tumor site in our study were found to be associated with the adequacy of the lymph node evaluation. The odds of having a low number of lymph nodes evaluated was higher in patients aged 60 years old and above than that in the patients aged 40 years old and younger (OR = 2.42; 95% CI = 1.29–4.53) (Table 2).

A systematic review in 2007 analyzed 17 studies that included 61,371 patients. As a result, it concluded that the number of lymph nodes examined was positively associated with survival of colon cancer patients at stages II and III^[10]. Moreover, several other studies have demonstrated that the number of the resected lymph nodes is an independent prognostic factor, particularly in patients at stage II of the disease^[8].

One explanation for this finding is that inadequate lymph node rerieval and its assessmant may incorrectly stage a node-positive patient as a node-negative one, which consequently results in inappropriate undertreatment^{[8, 11]}.

Some experts, however, believe that extensive lymphadenectomy might play therapeutic roles in improving tumor clearance and reducing the chance of metastatic spread through the lymphatic system, especially in patients at advanced stages of the disease^[8]. On the other hand, many authors disagree with this proposed mechanism, because a number of studies have failed to demonstrate that removal of a higher number of lymph nodes is associated with a better overall survival in patients with advanced-stage disease. Furthermore, a large study has examined the relationship between lymph node evaluation and node positivity using SEER (Surveillance, Epidemiology, and End Results) data from 1988 to 2008 and concluded that despite a significant increase in the number of evaluated lymph nodes in recent decades, this does not result in an overall shift towards higher staged cancers^[11]. This finding has questioned the role of ’upstaging‘ in improving the survival of the patients undergoing extensive lymphadenectomy.

Nonetheless, in terms of the majority of currently used guidelines, retrieval of a minimum of twelve lymph nodes is necessary to achieve accurate pathologic staging. Unfortunately, the recommended number of 12 is not always achievable. In fact, although the number of inadequate retrievals have significantly decreased over recent decades, they are still present in a consederable number of surgical cases^[11].

The published reports in the United Stated between 2005 and 2010 showed that despite all effeorts and recommendations in this regard, lymphadenectomy was still inadequate in 48% to 63% of surgical cases^[12]. A similar trend was also reported from many European centers. For instance, a report from Germany showed that in 73% of colon cancer and 58% of rectum cancer cases, the number of examined lymph nodes was less than 10^[13]. In addition, there are reports from England showing that lymphadenectomy was inadequate in 33% to 50% of colorectal cancer cases^{[14, 15]}.

It has been observed that several factors might affect the adequacy of lymph node retrieval or its assessment, including the expertise of the surgeon and the pathologist as well as some patient-related factors such as differing distributions of lymph nodes in colon and rectum. Other clinical and demographic charectersitics such as age, gender, race, body mass index, tumor T-stage, and type of surgery have also been reported in some previous studies to play roles in this regard^{[5, 6, 8, 16, 17]}.

Although many studies have found no relationship between age and the number of evaluated lymph nodes^[5], our results are in agreement with the findings of other studies, which conclude that older patients have a greater probability of having less than optimal lymph node retrieval^{[8, 17, 18]}. One explanation for this could be that extensive and time-consuming operations might not be feasible in older individuals due to the presence of comorbidities.

In our study, those patients with the primary tumor locations in descending colon and rectum had higher odds of receiving a report with a low number of lymph nodes examined compared to the patients with tumor locations in ascending and transverse colon (OR = 2.47; 95% CI 1.49 – 4.09 and OR = 2.37; 95% CI = 1.42–3.94, respectively) (Table 2).

Several other studies have demonstrated similar results^{[5, 18,19,20]}. In addition, many experts believe that lymph node retrieval is more difficult in rectal tumors, which may possibly be due to the lymph nodes being smaller^[8]. However, some studies have shown that patients with left colon tumors have a greater chance of optimal lymph node removal compared to patients with right colon tumors^[21].

Our results show that more than 12 dissected lymph nodes are associated with increased survival rate, and fewer than 12 dissected lymph nodes are correlated with decreased survival in colorectal cancer patients.

In this study, we found no relationship between the number of evaluated lymph nodes and different stage groups, that is, T-stage, gender, tumor grade, and tumor size.

In this study, we aimed to evaluate the adequacy of lymph node harvest in the patients with colorectal cancer who had been treated in a public referral center. Our results show that the number of evaluated lymph nodes was less than the standard number in more than half of the studied patients. Among various factors, older age and tumor locations in descending colon and rectum were found to be associated with suboptimal assessment of lymph nodes.