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Japanese Journal of Clinical Oncology Advance Access originally published online on November 7, 2005
Japanese Journal of Clinical Oncology 2005 35(11):645-650; doi:10.1093/jjco/hyi182
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© 2005 Foundation for Promotion of Cancer Research

Is there any Role for Sentinel Node Mapping in Colorectal Cancer Staging? Personal Experience and Review of the Literature

C. Codignola1, F. Zorzi2, A. Zaniboni3, S. Mutti1, A. Rizzi3, E. Padolecchia2 and G. B. Morandi1

1 Department of General Surgery, 2 Department of Pathology and 3 Department of Clinical Oncology, Casa di Cura Poliambulanza, Brescia, Italy

For reprints and all correspondence: Claudio Codignola, Via Breve 1, 25135 Brescia, Italy. E-mail: ccodi{at}tin.it

Received July 11, 2005; accepted September 20, 2005


   Abstract
TOP
 Abstract
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 References
 
Background: We explored the role of lymphatic mapping and sentinel lymphadenectomy (originally described for melanoma and breast cancer) in colon cancer. Pathologic techniques can successfully identify micrometastatic disease in lymph nodes, but they are not suitable for clinical routine use. We evaluated the role of sentinel node (SN) mapping in refining the staging of colorectal cancer.

Methods: A total of 56 open colorectal resections were performed, and Patent Blue V dye was injected under the serosa surrounding the tumor immediately after opening the abdomen. SNs were analysed by immunohistochemistry to find micrometastatic disease. A literature search for the role of SNs in colorectal cancer was also performed.

Results: We identified the SN in 100% of patients, with a mean of 2.02 SNs/patient (range 1–5). After immunohistochemical staining, we could upstage 21 out of 56 patients (37.5%), and we observed 10.7% false negative SNs (6/56 patients). Fewer than half of the articles described false negative rates of <15%, and most articles showed an upstaging rate of >5% of patients. These differences are probably the result of different sensitivities of the methods used in identifying the lymph node micrometastases.

Conclusions: SN mapping is an easy and cost-effective technique that holds promise and warrants further investigations.

Key Words: sentinel lymph node biopsy • colorectal surgery • colorectal carcinoma • lymphatic metastasis • colonic neoplasms


   INTRODUCTION
TOP
 Abstract
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 References
 
Although adjuvant chemotherapy has an established role in improving the prognosis of stage III colon cancer (1), the benefit for stage II patients remains controversial (2). We, therefore, need to establish prognostic markers capable of identifying which stage II patients might benefit from adjuvant treatment. Even with successful surgical intervention, approximately 20–25% of stage II colorectal cancer patients develop regional or distant metastases within 5 years of diagnosis (1,2), presumably owing to pathological understaging from missed micrometastases in lymph nodes (2), which are often <5 mm in size. Pathologic techniques, such as immunohistochemistry and RT–PCR analysis, can identify micrometastatic disease in lymph nodes. However, it is cost-prohibitive and highly time-consuming to ultrastage all the nodes in a given specimen, especially when the specimen contains multiple nodes. Here, we evaluate the role of sentinel node (SN) mapping in colorectal cancer staging.

Cabanas (3) first used the term ‘sentinel lymph node’ in 1977 for penile carcinoma, and the use of SN mapping has been validated for breast cancer and melanoma (4,5). SN biopsy can reduce surgical invasiveness by improving the patient's nodal staging, with subsequent restriction of unnecessary lymph node dissections in nodal-negative patients. However, the use of SN mapping in gastrointestinal cancers is not yet validated because of the high percentage of false negative, as well as patient- and tumor-specific differences in lymphatic drainage (6). Differences in technique also make interpretation of the outcomes challenging. In contrast, certain features of colorectal cancer are more amenable to SN mapping, including the presence of regular lymphatic drainage channels. Saha and co-workers (7) successfully used SN mapping to stage colorectal cancer patients, with a technique involving injection of a vital blue dye (Lymphazurin) subserosally around the primary tumor. The blue stained nodes (i.e. the SNs) were then analysed by pathologist en bloc with the resected colon specimen. Ultrastaging of the SN was performed by immunohistochemistry and/or RT–PCR, resulting in an upstaging of ~15–20% of stage II patients.

By reporting our data and reviewing scientific reports, we aim to evaluate SN mapping as it applies to colorectal cancer, including its indications, limitations, benefits and future directions.


   PATIENTS AND METHODS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSION
 References
 
PERSONAL EXPERIENCE
We studied 56 colorectal cancer patients (20 men, 36 women; aged 70.81 ± 11.33 years; range 42–91 years) who had undergone operation at our institution. Patient characteristics are summarized in Table 1. Informed consent was obtained before surgery in all cases. Eligibility criteria for patients included presence of histologically confirmed colorectal cancer, absence of a previous colon resection or major abdominal operation, and absence of liver metastases.


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  		Table 1. Patients and tumor characteristics

 
Standard open colon resection was performed in all 52 colon cancer patients, and a standard anterior colorectal resection was performed in the four patients with rectal cancer (all had cancer in the intraperitoneal portion of the rectum). After opening the abdominal wall, the minimal number of surgical maneuvers necessary to reach the tumor site were performed. Subsequently, 1–2 ml of vital dye (Patent Blue V)was injected subserosally around the tumor, taking care to prevent dye leakage into the surgical field and the bowel lumen. Within 5–10 min, blue staining of the lymphatic vessels reached one or more nodes (the SN), which were tagged with a stitch for pathological analysis.

The SN mapping technique as described by Saha and co-workers (7) for in vivo determination of SN was used.

Subsequently, standard colon resection with complete lymphadenectomy was used. Pathologic analysis of the specimens included microscopic examination of size, shape, diameter, depth of invasion, histologic grade and distal margin of the tumor. Hematoxylin and eosin (H&E) staining was used for standard lymph node assessment. After a routine pathological examination with H&E of the SNs, they were studied in a deeper way also. SNs were bivalved and sectioned by microtome to obtain three pairs of 4 µm slices. We discarded 40 µm of tissue between every slice to avoid artifacts. Each slice was stained with H&E and cytokeratin immunohistochemistry (cytokeratin Cam5.2; Becton Dickinson, San Jose, CA, USA) to recognize neoplastic cells. Slice analysis was continued until a positive neoplastic signal was seen, or when up to 10 slice pairs had been analysed. Nodes containing even a single neoplastic cell were counted as positive.

Patients were treated with adjuvant chemotherapy according to standard protocols, and complete follow-up regarding survival and cancer recurrence was performed. Disease-free survival was evaluated using the Kaplan–Meier survival analysis, with the log-rank test to determine statistical significance between SN negative and SN positive only patients. Values for P-value of <0.05 were considered to be statistically significant. SPSS software (Statistical Package for the Social Sciences, version 8.0; SSPS Inc., Chicago, IL, USA) was used for statistical analyses of the data.

REVIEW OF THE LITERATURE
A literature search was performed in PubMed from 1999 to 2005 (www.pubmed.com), searching articles in English only (search terms: SN mapping colorectal cancer). A total of 18 primary research articles about SNs in colorectal cancer were found. Some groups reported several studies with the same patients; in those cases, only their largest studies were reported.

There are two different techniques for mapping SNs: in colon cancer the dye injection is made in the subserosal layer during operation, whereas in rectal cancer the dye injection is made in the submucosal layer using a proctoscope before the operation.


   RESULTS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSION
 References
 
We were able to visualize SNs in all 56 cases (100%). The mean number of retrieved lymph nodes/patient was 21.0 (range 6–47), and the mean number of SNs/patient was 2.0 (range 1–5). We observed 1 (1.79%) patient with a T1 tumor, 12 (21.43%) patients with T2, 35 (62.50%) patients with T3 and 8 (14.29%) patients with T4 tumors (Table 1). The histologic grade of cancer was well differentiated in 7.14% of cases, 87.50% moderately differentiated and 5.36% poorly differentiated.

According to standard TNM classification and staging, we had 8 (14%) patients in stage I, 25 (45%) patients in stage II, 20 (36%) patients in stage III and 3 (5%) patients in stage IV. The use of SNs in patient staging led to one of the following four scenarios (Table 2):

  1. True positive: patients with cancer cells both in SNs and in conventional non-SNs, 16 (28.6%) patients.
  2. True negative: patients with no cancer cells in either sentinel or non-SNs, 13 (23.2%) patients.
  3. True positive in only SN: patients with cancer cells in SNs only, 21 (37.5%) patients.
  4. False negative: patients with cancer cells in non-SNs only, 6 (10.7%) patients.
In contrast to the relatively small number of skip metastases seen (false negative patients; 6/56), a large group of patients (21/56) could be moved to a higher stage with SN analysis.


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  		Table 2. Sentinel node analysis data

 
Revised staging according to SN analysis showed 3 (5.4%) patients in stage I, 10 (17.9%) in stage II, 40 (71%) in stage III and 3 (5.4%) in stage IV (Table 3). We did not identify aberrant lymphatic drainage with SN mapping, unlike in previous works (8–10).


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  		Table 3. Stage migration after sentinel node analysis

 
During follow-up (mean 43.8 months; range 1–73), we observed four deaths and eight recurrences in our population. All patients with nodal involvement according to the revised staging received adjuvant chemotherapy (mainly 5-FU + leucovorin-based). Disease-free survival curve for SN positive only patients versus stages I and II SN negative patients is depicted in Fig. 1.



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  		Figure 1. Disease-free survival curve for sentinel node (SN) positive only patients (SN positive) versus stages I and II SN negative patients (SN negative). Solid line indicates patients with positive SNs, whereas dotted line indicates patients with stages I and II negative SNs.

 

   DISCUSSION
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSION
 References
 
In a report from 1998, Joosten and co-workers (11) could identify the SN in only 70% of 50 consecutive patients, and with a sensitivity of only 45%. Additional immunohistochemical staining of the SNs from node-negative patients identified two micrometastases in 15 patients, upstaging 4% (2/50) of the whole group. They, therefore, concluded that SN mapping was not useful in staging colorectal cancer. Two possible reasons for mapping failure in this study are (i) that SNs were not tagged immediately after detection (blue dye travels very quickly and can stain other nodes beyond the SN) and (ii) all blue nodes detected (up to 16) were classified as sentinel, in contrast with the original definition of SNs (i.e. the first 1–3 blue nodes) (5). The same year, Cserni and co-workers (12) observed similar negative results with Patent Blue V dye injection during the operation. The pathologist managed to identify SNs in most (96%) of the patients, but with a poor sensitivity (62%). Wiese and Saha (13,14) were the first to describe successful lymphatic mapping using blue dye (isosulfan = Lymphazurin). They identified SNs in almost all (99–100%) patients, with a sensitivity of 91 and 92%.

Many studies reporting positive results with lymphatic mapping, usually using blue dye, appeared after 2000. Lymphazurin seems to be a better dye than Patent Blue V for SN identification (11,12,15–18). Several authors have used an ex vivo, post-excision technique, where dye is injected into the submucosal layer after opening the specimen at the antimesenterial border (19,20). Many reports suggest that lymphatic mapping is much more difficult to perform in rectal cancer patients because the mesorectum lacks a serosal layer and is more bulky than the mesocolon (which is usually flat) (Table 4).


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  		Table 4. Review of the literature and personal experience

 
There also are reports of successful mapping during laparoscopic colectomy, where blue dye was injected endoscopically in the submucosal layer (9,10,21). In some cases there was an ectopic SN (i.e. a node outside the planned resection margins) (8–10). Most studies included immunohistochemical staining of the SN for pathological analysis and showed an upstaging rate between 2 and 20%. Studies using RT–PCR analysis showed an upstaging rate between 8 and 30% (8,15,22,23).

Although the majority of studies suggest that SN mapping is a useful clinical tool, a recent multicenter study indicated some potential challenges in its wider application (24). The study enrolled 91 surgical patients (79 with colon cancer) were operated on by 25 surgeons at 13 institutions. Patients with cancer of the rectum were excluded. They could successfully locate the SN in 92% of cases (66/79) but with a very high percentage of false negative SNs (54%). This study did have a number of limitations, however, including a small patient number per surgeon (suggesting the technique might not have been consistently applied), and the lack of immunohistochemistry for identifying metastases (H&E staining cannot reliably detect single-celled metastases).

Overall, the literature suggests that this technique can be successfully used for colorectal cancer, with better results in colon cancer, and can reveal nodes previously missed by regular pathologic examination, including ectopic SNs.

Our experience confirms the feasibility and clinical usefulness of this method. We observed a high detection rate of stained nodes and found that surgical dissection of the fatty mesenteric layer leads to successful node detection even in obese patients. We have studied the impact of SN ultrastaging in disease-free follow-up. We found that among the 21 patients with positive SNs only, there were two recurrences (local or distant) (9.5%), whereas in the 13 negative SN patients, the recurrence rate was 7.7% (1/13 patients). Interestingly, the subset of SN negative stages I and II patients is free from recurrences, whereas the subset of SN positive patients accounts for two recurrences (Fig. 1). Although patient numbers are too small to detect statistical significance, these data suggest that SN might be a useful predictor of clinical outcome. In addition, this technique is safe, fast and inexpensive, and can be performed in every surgical clinic, with a short learning curve (about 10 cases) and a final identification rate of almost 100%.

The cases of false negative staging we observed might be owing to the following scenarios:

  1. obstruction of lymphatic ducts by tumors as described in breast cancer (25);
  2. sampling errors during pathologic examination;
  3. procedure faults and/or errors in injecting the blue dye (injection is very important for the correct visualization of the SN).
This false negative phenomenon, however, is not as dangerous for downstaging as in other tumors, as a classic resection is always performed. The greatest impact on staging is not the presence of ectopic SNs, but a thorough examination of the SN using special staining methods.

Modern techniques, such as immunostaining and RT–PCR, combined with the SN technique make the whole staging procedure much faster and less costly. However, ultrastaging techniques are controversial. RT–PCR allows examination of the whole lymph nodes and could be useful for defining a threshold value of minimal tumor load. All studies based on RT–PCR analysis have found a direct correlation between micrometastases and a lower disease-free survival (Table 5). Furthermore, only a subset of cancer patients with micrometastases will develop overt recurrent tumors. Analysis of the clonogenic capacity of the neoplastic cells found in the lymph node micrometastases, as well as the genotypic/phenotypic characteristics and microenvironmental factors that may influence migration, survival and growth of these cells, are important prognostic factors (26,27). For example, isolated tumor cells in mesenteric nodes indicate a worse prognosis in patients with stage II colon cancer (28). The improved nodal staging by means of SN mapping and subsequent selective application of immunohistochemical staining and RT–PCR techniques results in an upstaging of up to 20% for patients with lymph nodal micrometastasis. Thus, focused analyses of the SN could represent an accurate, timely and cost-effective means of reducing the understaging associated with conventional pathological examinations.


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  		Table 5. Prognostic significance of micrometastatic lymph nodes

 

   CONCLUSION
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
References
 
The principal advantages of SN mapping are that it is inexpensive, safe, easy and quick, and can be performed in almost all surgical centers. Although this technique has significant potential for ultrastaging colorectal cancer, there is some uncertainty about the outcomes for upstaged node-positive patients and the criteria for the use of chemotherapy. Further prospective and follow-up studies are needed to prove these intriguing hypotheses.


   References
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 References
 
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