|Ahead of print publication
Sentinel lymph node mapping in colorectal cancers with radioactive tracer; is it an efficient method?
Seyed Hassan Babaee1, Mehdi Jabbari Nooghabi2, Ramin Sadeghi3, Abbas Abdollahi4, Amer Falsafi1, Mehrdad Fakhlaei1, Zahra Gholami1
1 Endoscopic and Minimally Invasive Surgery Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
2 Department of Statistics, Faculty of Mathematical Sciences, Ferdowsi University of Mashhad, Mashhad, Iran
3 Nuclear Medicine Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
4 Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
|Date of Submission||15-Mar-2017|
|Date of Decision||17-Oct-2019|
|Date of Acceptance||01-Dec-2019|
|Date of Web Publication||09-May-2020|
Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad
Source of Support: None, Conflict of Interest: None
Context: The sentinel lymph nodes (SLNs), as most other regions, are prone to tumoral invasion. In colorectal cancers, they can help the higher levels of pathological examination techniques.
Aims: We attempted to investigate the efficiency of the use of radioactive tracer in identifying SLNs in colorectal cancers using the same pathological technique.
Settings and Design: This cross-sectional, single-center study was carried out from 2014 to august 2016 at Mashhad University of Medical Sciences.
Subjects and Methods: The study population included 100 patients with colorectal cancers. We used a radioactive tracer to detect SLNs and to compare the number and involvement of SLNs and non-SLNs generally and in terms of the tumor site. For pathological study, we used the same conventional method in both the groups.
Statistical Analysis Used: Statistical analysis was performed using SPSS 22.0 software (IBM Corp., Armonk, NY, USA) with Chi-square and Fisher's exact test, Student's t-test, ANOVA test, Mann–Whitney U-test, and Kruskal–Wallis test.
Results: SLNs were detected in 89 of 100 patients. All the remaining 11 patients had T4 lower rectal cancer and the injection was performed ex vivo. We noted ten cases of upstaging due to SLN mapping and nine cases of false negative. Thus, the sensitivity was found to be 43.75%at and the accuracy was 78.65%.
Conclusions: We used the same traditional method in both the groups, and our sensitivity, accuracy and upstaging rate were fewer than similar studies. Our recommendation for further studies is to use intensive SLN biopsy method in both groups of SLNs and non-SLNs.
Keywords: Colorectal neoplasms, radioactive tracers, sentinel lymph node biopsy
|How to cite this URL:|
Babaee SH, Nooghabi MJ, Sadeghi R, Abdollahi A, Falsafi A, Fakhlaei M, Gholami Z. Sentinel lymph node mapping in colorectal cancers with radioactive tracer; is it an efficient method?. J Can Res Ther [Epub ahead of print] [cited 2020 Aug 10]. Available from: http://www.cancerjournal.net/preprintarticle.asp?id=284076
| > Introduction|| |
Colorectal cancers, which are characterized by the symptoms of bowel obstruction, rectal bleeding, anemia, and altered bowel habits, are the third most common cancer worldwide and its prognosis is highly dependent on TNM staging.
According to the TNM staging system, the survival of patients with colorectal cancer is different and this staging is too much dependent on regional lymph node involvement. As in Stage I and II, where there is no regional lymph node involvement, 5-year survival is 93% and 82%, respectively, while in Stage III cancers, the 5-year survival shows a reduction of <59%. Lymph node involvement requires adjuvant chemotherapy. This fact makes it critical to careful evaluation of lymph nodes in colorectal concerts.
Sentinel lymph node (SLN) concept was first described in 1977 by Cabana et al. It was introduced as the first lymph node which routes, and consequently, the first lymph node is involved with cancer.
Afterward, it was widely used in the diagnosis and treatment of breast cancers and melanomas with proven efficiency.,
Hence, the SLNs, as most of the other regions, are prone to tumoral invasion. In colorectal cancers, likewise, they can help the higher levels of pathological examination techniques.
In this study, we attempted to investigate the efficiency of the use of radioactive tracer in identifying SLNs in colorectal cancers.
| > Subjects and Methods|| |
This cross-sectional, single-center study was carried out from January 2014 to August 2016. The study was approved by the Ethics Committee of Mashhad University of Medical Sciences. One hundred patients with cancer of the colon and rectum referred to Ghaem and Omid hospitals in Mashhad were enrolled in the study. The entire process of the diagnosis and treatment was conducted by a single surgeon. The diagnostic process included colonoscopy and biopsy, computed tomography scan of the abdomen and pelvis with intravenous and oral contrast, and plain chest X-ray.
The exclusion criteria included pregnancy, Stage IV cancers and cancer recurrence, and having a history of an allergic reaction to radioactive tracing material.
The study variables included age, gender, tumor characteristics (tumor site, T and N), methods (in vivo, ex vivo), number of lymph nodes detected, number of SLNs, non-SLN, and SLN involvement.
Radioactive tracer injection protocol
In lower rectum cancers just before the surgery, 18.5 MBq (0.5 mCi) Tc-99 m antimony sulfide colloid in 0.2 ml saline was submucosally injected; and in the upper, middle, and lower rectum and colon, after the onset of surgery, a subserosal injection was performed around the tumor.
Colon and rectal surgery was performed using the classical method. The colorectal mesentery was completely removed with tumor and then tissue samples were evaluated out of the abdomen. A probe was slowly advanced through the injection site into the lateral of the mesentery and lymph node with the highest radioactivity and all with >10% of the radioactivity hottest gland was removed and the anatomical location of all nodes removed was recorded. The procedure was done in two ways of ex vivo orin vitro and in vivo. In in vivo, radioisotope was injected during surgery and when the sample was not yet removed from the body. It means we had 20 min time to extract the samples from the tissue and in case there is still systemic circulation, so it seems to help the further spread of radioactive material to the lymph nodes. Ex vivo injection was performed after the removal of the sample from the tissue and complete cessation of blood flow. Thereafter, we softly massaged the injection site for 2 min, and after an average of 20 min, we searched for hot lymph nodes. The advantage of this method is that the surgeon could perform the injection out of the operative field with greater dominance (mastery) and without imposing possible side effects due to the systemic absorption of radioisotopes by the body.
Statistical analysis was performed using SPSS 22.0 software. To compare qualitative variables, we used Chi-square and Fisher's exact test, while for quantitative variables, parametric or nonparametric tests of Student's t-test, ANOVA test, Mann–Whitney U-test, and Kruskal–Wallis test were used.
| > Results|| |
SLNs were detected in 89 of 100 patients, and in 11 patients, SLN detection was not possible (detection rate: 89%). All the remaining 11 patients had T4 lower rectal cancer and the injection was performed ex vivo orin vitro[Table 1]. Hence, the detection rate forin vivo method was 100% and for ex vivo was 80%, and it was 100% in colon, upper rectum, and middle rectum and was 66.66% in lower rectal cancers. In other words, the detection rate was 57.69% in lower rectal cancers with ex vivo method and this amount for other situations was 100%. The study patients' age ranged between 22 and 78 (mean: 51.36) years [Table 2]. Fifty-two (52%) cases were female and 48 (48%) were male. Overall, 238 SLNs were detected in 89 patients, with an average of 2.6742 lymph nodes per patient. The maximum number was 13 belonged to a patient with middle rectal cancer, and the minimum was one SLN. Regarding the type of cancer, the mean number of SLNs detected in the colon and upper, middle, and lower rectum was, respectively, 2.4634, 2.6250, 5.0556, and 1.1364 nodes. Thein vivo method was used in 45 patients, and the ex vivo method was used in 55 cases.
According to our study, due to the ease of performing, it revealed a predominance ofin vivo method in colon and upper and middle rectal cancers; there was also a predominance of ex vivo method in lower rectal cancers.
Of the patients with successful identification of SLNs, in 17 (19.1%) cases, lymph node metastases were observed. Hence, in colon cancer, there were three of 41 cases of SLN involvement. The involvement was also observed in six of eight cases with upper rectal cancer and 6 of 18 patients with middle rectal cancer, while this figure was 3 of 22 for lower rectal cancers. The maximum involvement was seen in the upper rectum (75%) and the minimum in the colon (7.3%).
In terms of tumor size, T3 was determined in 49 cases, followed by T2 in 23 cases [Table 2].
Overall, involvement was not detected in 63 of 89 patients, neither in SLNs nor non-SLNs. While in seven patients, both SLNs and non-SLNs were involved. In ten cases, there was SLN involvement with no non-SLN tumoral metastasis (upstaging). The results of lymph node analysis are demonstrated in [Table 3]. As well, nine cases with non-SLN involvement had no SLN involvement (false negative). Thus in this study, the sensitivity was 43.75% and the accuracy was 78.65%.
It was found that in colon cancers of 41 cases, 38 cases were SLN negative and three cases were SLN positive. Furthermore, we had 37 non-SLN negatives and four non-SLN positives. It indicated one case of SLN involvement despite intact non-SLN (upstaging). Furthermore, we found two cases with non-SLN involvement despite no SLN tumoral metastasis (false negative). Hence, in colon cancers, the sensitivity was 50% and the accuracy was 92.68%.
Furthermore, we found that in upper rectal cancers, we have three upstaged cases by our method of SLN mapping and there is not any false negative in these cases. Thus, in the upper rectum cancers, the sensitivity was 100% and the accuracy was 62.50%.
In patients with middle rectal cancers, we had three cases with upstaging and four false-negative cases. Hence, in lower rectal cancers, the sensitivity was 33.33% and the accuracy rate was 61.11%.
In lower rectal cancers, there were three upstaged patients and three false negatives. Hence, in lower rectal cancers, the sensitivity was <0.01% and the accuracy rate was 72.72%.
| > Discussion|| |
About half of patients with colorectal cancer at an early stage and without lymph node involvement are detected, for whom a curative surgical treatment is performed. However, 20% to 30% of them are expired in the first 5 years after surgery due to the local recurrence with distant metastasis.
This could be related to the presence of micrometastasis in lymph nodes and occult tumoral cells that are hidden from the eyes of pathologists in conventional methods.
Neoadjuvant chemotherapy may improve the prognosis of a node-positive patient to 30%.
According to the American Joint Committee on Cancer (AJCC), it requires 12 negative lymph nodes for the confirmation of the absence of regional lymph node involvement.
There are some ways to improve the staging of colorectal cancer and commenting on the involvement of the regional lymph nodes, such as serial sectioning pathology and immunohistochemistry (IHC). The use of these methods on all regional lymph nodes, sometimes their number is significant, seems impossible because it requires too much time and cost. It was attempted to find a way to limit the number of samples without reducing the efficiency and accuracy of the lymphatic study.,,
The concept of SLN was first introduced in 1960 by Gould et al. in conjunction with parotid cancer and Cabana et al. in relation to the penis cancers, and then, it was broadly used in diagnostic and therapeutic processes related to breast and melanoma cancers. Hence, complications of wide lymphatic dissection are avoided largely., This concept for colorectal cancers for the first time was presented by Joosten in 1999. Many studies have advocated that lymph node status has the greatest impact on cancer prognosis. Moreover, lymph node involvement necessitates the need for complementary oncologic therapies. There are a high number of patients with a 30% rate that due to being in lower stages are not candidates for chemotherapy. They sometimes present with recurrence and distant metastasis implying the fact that the staging has been a false negative, and that the micrometastases and isolated tumoral cells in lymph nodes have been hidden from the eyes of the pathologist., This will necessitate the use of the intensive pathologic examination (multi-sectioning and immunohistochemical markers). Of course, using these methods for all lymph nodes that sent due to the time consuming and high cost of these tests is not possible. Hence, SLN biopsy (SLNB) has been suggested to limit the number of samples.
AJCC and the Union for International Cancer Control have rejected the upstaging for the presence of micrometastases and isolated tumoral cells in lymph nodes,, and many studies could not confirm the efficacy of SLNB for colorectal cancers. Hence, the effectiveness of SLNB in colorectal cancers is still controversial.,
Due to low sensitivity and high false-negative rate, SLN mapping in colorectal cancers still cannot be used for therapeutic purposes.
The efficacy of SLNB, especially using a radioactive tracer, has not been yet confirmed., In this study, we attempted to investigate the effectiveness of the use of SLNB for colorectal cancers by radioisotopes tracer, and for all SLNs and non-SLNs, the pathologic conventional method was used to provide a better comparison and to avoid any bias caused by unequal conditions. Of course, in case of using intensive pathologic examination (serial sectioning and IHC markers), the sensitivity, accuracy, and upstaging rate will be more satisfactory. However, to the best of our knowledge, the use of an intensive method for non-SLNs could also increase the false-negative rate by the same amount, and consequently, decrease the scientific value of the study, and this is remaining conflicts over the use of SLNB. Hence, we favored to create an equal condition. According to our findings, to achieve real efficiency, accuracy, and sensitivity of SLNB, for both types (SLN and non-SLN), at least in the research stages, we should apply equal pathological methods and we should use complicated methods such as IHC and other intensive studies only when we can prove the effectiveness of SLN mapping from the base, first.,,,
In our study, despite the results show that the detection rate 100% byin vivo and 80% by ex vivo, no comparison was made between thein vivo and ex vivo methods. However, similar studies have not found a significant difference between the results of these two methods.
In a quick review of previous similar studies that used only radioactive tracer in SLNB, have been reported false-negative rate of 8% to 20% (11% in our study). In comparison with studies that used blue dye in SLNB, they had more false negatives and less sensitivity and specificity too. This difficulty can be attributed to the use of radioactive tracer and Gama probe and requirement of coordination with the nuclear medicine department (to prepare radioactive tracer) and, of course, lack of experienced operator. This will be gradually improved with the increase of researchers' experience and improvement in equipment needed and the resolution of technical problems.
| > Conclusions|| |
We use a traditional method for both the groups, and our sensitivity, accuracy, and upstaging rate were fewer. Our recommendation for further studies is to use intensive SLNB method for both groups of SLNs and non-SLNs. It makes the comparison in equal situations. Moreover, it is better to do this with a higher population, using blue dye or a combination of blue dye and radioactive tracer.
The results described in this article formed part of a thesis submitted by the first author for a postgraduate degree in general surgery. The authors gratefully acknowledge the contribution of Ms. M. Hassanpour for editing the manuscript.
Financial support and sponsorship
The study was supported by the Vice Chancellor for the Research of Mashhad University of Medical Sciences.
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]