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Annals of Surgical Oncology 8:150-157 (2001)
© 2001 Society of Surgical Oncology

ORIGINAL ARTICLES

Validation of Lymphatic Mapping in Colorectal Cancer: In Vivo, Ex Vivo, and Laparoscopic Techniques

Thomas F. Wood, MD, Sukamal Saha, MD, Donald L. Morton, MD, George J. Tsioulias, MD, DMSc, Decio Rangel, MD, William Hutchinson Jr., MD, Leland J. Foshag, MD and Anton J. Bilchik, MD, PhD

From the John Wayne Cancer Institute (TFW, SS, DLM, GJT, DR, WH, LJF, AJB), Santa Monica, California and the Department of Surgery (SS), McLaren Regional Medical Center, Michigan State University, Flint, Michigan.

Correspondence: Address correspondence to: Anton J. Bilchik, MD, PhD, John Wayne Cancer Institute, 2200 Santa Monica Boulevard, Santa Monica, CA 90404; Fax: 310-449-5261; Email: bilchika{at}jwci.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: The use of lymphatic mapping (LM) is being investigated to improve the staging of colorectal cancer (CRC) and thereby identify patients who might benefit from adjuvant chemotherapy. This study evaluated in vivo, laparoscopic, and ex vivo approaches for the ultrastaging of CRC.

Methods: Seventy-five CRC patients were enrolled in a study of LM with peritumoral injection of isosulfan blue dye. LM was undertaken during open colon resection (OCR) in 64 patients, during laparoscopic colon resection (LCR) in 9 patients, and after specimen removal (ex vivo) in 2 patients. Ex vivo LM was also undertaken in 6 patients after unsuccessful in vivo LM. All nodes were examined by hematoxylin and eosin (H&E) staining; in addition, sentinel lymph nodes (SNs) were multisectioned and examined by immunohistochemical staining with cytokeratin (CK-IHC).

Results: At least one SN was identified in 72 patients (96%). In vivo LM identified SNs in 56 of 64 (88%) patients undergoing OCR and in 9 of 9 (100%) patients undergoing LCR. Ex vivo LM was undertaken as the initial mapping procedure in 2 cases of intraperitoneal colon cancer and after in vivo LM had failed in 6 cases of extraperitoneal rectal carcinoma; an SN was identified in 7 of the 8 cases. Focused examination of the SN correctly predicted nodal status in 53 of 56 OCR cases, 9 of 9 LCR cases, and 6 of 7 ex vivo cases. Multiple sections and CK-IHC identified occult micrometastases in 13 patients (17%), representing 10 OCR, 1 LCR, and 2 ex vivo cases.

Conclusions: LM of drainage from a primary CRC can be accurately performed in vivo during OCR or LCR. Ex vivo LM can be applied when in vivo techniques are unsuccessful and may be useful for rectal tumors. During LCR, colonoscopic injection can be used to mark the primary tumor and define the lymphatic drainage so that adequate resection margins are obtained. These LM techniques improve staging accuracy in CRC.

Key Words: Colorectal carcinoma • Sentinel node • Lymphatic mapping • Staging • Laparoscopic colon resection • Ex vivo.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Colorectal cancer (CRC) is the second leading cause of deaths from cancer in the United States. The 5-year survival rate is high (90%) after treatment of American Joint Committee on Cancer (AJCC) stage I CRC but decreases substantially as the disease progresses to stage II (75%) and stage III (50%).1 Hence, the presence of lymph node metastasis is one of the most important prognostic factors.

Approximately one third of patients initially diagnosed with AJCC stage I or II CRC develop systemic disease despite "negative" lymph nodes. This implies that these patients have occult disease not detected by current techniques. Previous studies have demonstrated that lymph node micrometastases documented by ultrastaging correlate with poorer survival.2,3 Because the average CRC resection specimen contains 15 or more lymph nodes, the use of ultrastaging techniques on each lymph node would be labor and cost intensive. Therefore, a means of focusing an examination on the lymph nodes most likely to contain metastases would be advantageous.

Morton and colleagues4 popularized the sentinel lymph node (SN) concept in melanoma. Giuliano and co-workers5 later applied the concept in breast cancer. Because the first ("sentinel") lymph nodes to receive the lymphatic drainage from the primary tumor are the most likely to contain metastasis, examination of these SNs could be used to determine which patients should not be subjected to the morbidity associated with complete lymphadenectomy. More recently, Bilchik et al.6 and Saha et al.7 have applied the lymphatic mapping (LM) technique to identify SNs in patients with CRC. However, unlike in melanoma and breast cancer, LM in CRC is not used to limit the extent of lymph node dissection, but rather to improve staging by a focused ultrastaging examination of the SNs.

In our early experience using LM in CRC (unpublished data, 1999), we successfully mapped the SN in more than 90% of cases, and most SNs were identified during open colon resection (OCR). One limitation of the technique, however, involved failures of LM for rectal tumors below the peritoneal reflection. Unpublished data from investigators at the University of Hawaii (JH Wong, May, 1999) indicate that LM of the drainage from a CRC can be performed ex vivo, i.e., after the tumor has been removed. We hypothesized that ex vivo LM might be useful when in vivo LM failed to identify an SN, especially in patients with rectal tumors, and that the approach could be applied during laparoscopic colon resection (LCR). This study expanded our initial experience with in vivo LM, and it evaluated the potential of ex vivo and laparoscopic LM to improve staging of CRC.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Between August 1996 and February 2000, 75 patients with clinically localized CRC were enrolled in a study of LM undertaken in vivo during OCR or laparoscopic colon resection (LCR), or ex vivo after the tumor had been resected. Informed consent was obtained prior to surgery.

In Vivo Techniques
Laparotomy and Routine Abdominal Exploration
The tumor was localized. After resectability had been determined and before mobilization of the colon, .5–1 cc of isosulfan blue dye (Lymphazurin, Ben Venue Laboratories, Inc., Bedford, OH) was carefully injected subserosally around the periphery of the tumor using a tuberculin syringe (Fig. 1). The dye traveled from the injection site along the lymphatics to the SN(s) typically within 30–60 seconds. Occasionally gentle dissection of the mesentery was performed to trace the lymphatic path to the SN. Each blue-stained node was marked with sutures, and the colectomy performed in the standard fashion, including all blue nodes in the specimen. The specimen was submitted for pathologic review. .



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  		FIG. 1. A tuberculin syringe is used to inject isosulfan blue dye subserosally around the periphery of the tumor. The blue dye immediately flows in the lymphatic channels toward the SN(s).

 
Laparoscopy/Colonoscopy
Patients were placed on the operating table in the low lithotomy position. The abdomen was insufflated. Laparoscopic abdominal exploration was performed to confirm suitability for LCR, and operative ports placed in appropriate locations for the specific procedure planned. The bowel was run using endobabcocks. The appropriate segment of bowel was mobilized by sharp dissection of the peritoneal attachments. The bowel was clamped distal to the tumor and colonoscopy performed. The tumor or polypectomy site was visualized and transilluminated (Fig. 2A) and LM was performed. The site was injected submucosally with .5–1 cc of blue dye via colonoscope. The site of the primary tumor injection was visualized by the laparoscope (Fig. 2B). The appropriate segment of colon and mesentery was exposed. Under the magnification of laparoscopy, the blue dye was followed from the primary tumor along the lymphatics to the SN(s). Each SN was marked with a clip or suture. A minilaparotomy was then performed and any additional SNs marked with sutures. The bowel resection and anastomosis were performed extracorporeally. All blue nodes and lymphatics were included in the mesenteric resection (Fig. 3). The specimen was submitted for pathologic review.



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  		FIG. 2. (A) Colonoscopic transillumination of the tumor/polypectomy site during laparoscopy. (B) Isosulfan blue tattooing of the tumor site after colonoscopic injection during laparoscopy. Note the lymphatic channel running inferior to the blue tattoo.

 


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  		FIG. 3. LM undertaken during LCR of a T1 cecal carcinoma reveals blue-stained lymphatic channels running from the primary tumor site to the SN deep at the base of the mesentery. Minilaparotomy has been performed and the specimen delivered extracorporeally. Arrows indicate the lymphatic channel superiorly and inferiorly as it enters the SN (marked with a suture and clips).

 
Ex Vivo Technique
The ex vivo technique was used either as a primary LM procedure, or secondarily for failed in vivo attempts at LM. After routine completion of the colectomy, the specimen was immediately taken to a side table. Isosulfan blue dye in a volume of 1–2 cc was then carefully injected subserosally around the tumor using a tuberculin syringe. The dye was visualized as it traveled from the primary site along the lymphatic channels to the SN(s) within the mesentery (Fig. 4). Each SN was marked with a suture. The specimen was submitted for pathologic review. .



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  		FIG. 4. Ex vivo LM identified SNs (arrows) in the mesentery. Injection of isosulfan blue dye was undertaken at a side table after the specimen had been removed from the body.

 
Histopathology Protocol
Pathologic review entailed routine microscopic analysis of the tumor, margins and all lymph nodes via hematoxylin and eosin (H&E) staining. In addition, each marked SN was examined by a focused technique originally developed for the examination of SNs draining primary breast carcinomas.8 The pathologist bisected or sectioned each SN into slices no thicker than 2–3 mm. Paraffin sections, each approximately 4 µm thick, were cut at two levels separated by 200 µm. One section from each level was stained with H&E and another with CK-IHC. A false-negative SN was defined as an SN that contained no tumor cells when one or more nonsentinel nodes in the specimen were tumor-positive.

Immunohistochemical Staining
Paraffin sections for CK-IHC were placed on charged slides (Superfrost Plus M6416-plus, Baxter Diagnostics Inc, McGaw Park, IL). A standardized procedure used an automated immunostainer (Ventana ES, Ventana Medical Systems, Tucson, AZ) with enzyme digestion (Protease 1) of tissue sections for 8 minutes and AE-1/AE-3 CK antibody (Dako Corporation, Carpinteria, CA) staining (1:200 dilution) for 32 minutes. Diaminobenzidene was the chromogen. IHC stains were interpreted according to strict criteria that required strong immunoreactivity combined with microanatomic and cytologic features compatible with CRC.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The 75 study patients represented a male:female ratio of 30:45 and had an average age of 68 years (range, 28–97 years). Primary tumors were in the right colon (n = 24), sigmoid colon (n = 18), rectum (n = 14), cecum (n = 10), left colon (n = 5), and transverse colon (n = 4). LM identified at least one SN in 72 (96%) patients. The average number of SNs identified was 2 (range, 1–4), and the average number of nodes in each CRC specimen was 15 (range, 2–28). In 7 cases, LM demonstrated primary lymphatic drainage to SNs outside the margins of conventionally planned resections. In each of these cases the operative procedure was altered (Table 1). For example, during four of the LCRs, an SN was mapped deep at the base of the mesentery, and the resection was extended to encompass this area. In two other right colon carcinomas, LM demonstrated SNs to the left of the middle colic vessels, and extended right hemicolectomies were performed to include the SNs in the mesentery of the transverse colon.


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  		TABLE 1. Unexpected lymphatic drainage in 7 patients undergoing LM for CRC
 
Overall, focused examination of the SNs correctly reflected the tumor status of the nodal basin in 68/72 (94%) cases (Table 2). Of the 35 patients with nodal metastases, 30 had positive SNs; thus the sensitivity of the SN as an overall indicator of nodal status was 88%. Thirteen (17%) of the 75 patients had occult nodal micrometastases identified only during a focused examination of the SN (Table 3); five tumors were upstaged by examining multiple sections of an SN, and the eight remaining tumors were upstaged by the results of CK-IHC. Another tumor was upstaged when micrometastasis was identified by routine H&E staining of an aberrantly positioned SN. The patient, who had a right colon cancer, underwent extended right colectomy (see above) after LM identified an SN in the mesentery of the transverse colon, left of the middle colic vessels. This SN was the only positive node of 18 in the resection specimen. The SN was the only positive node in 17 of the 75 cases; in 11 of these cases, the positive SN was demonstrated only after the focused pathologic examination (Table 3).


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  		TABLE 2. Technical success rates of in vivo and ex vivo LM techniques
 

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  		TABLE 3. Node positive and SN only positive cases
 
Tumor (T) stage correlated with increasing probability of node positivity (P = .0001, Wilcoxon sign rank test) (Table 4). Although only 1 of 14 (7%) T1 tumors and 7 of 22 (32%) T2 tumors had positive nodes, 22 of 33 (67%) T3 and 5 of 6 (83%) T4 tumors were associated with nodal metastasis. Similarly, advancing T-stage correlated significantly with SN positivity (P = .004, Wilcoxon sign rank test).


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  		TABLE 4. Relationship of tumor (T) stage to nodal status
 
In Vivo Techniques
In 64 patients, LM was undertaken during OCR (Table 2). In 56 of these cases (88%), at least one SN was identified (range, 1–4). Of the 8 unsuccessful cases, 7 were rectal tumors below the peritoneal reflection and 1 was a right colon tumor. The tumor status of the SN was an accurate indicator of nodal status in 53 of the 56 patients (95%), and focused examination of this node upstaged CRC in 10 patients.

In nine patients, LM was undertaken during LCR (Table 2). In all of these cases, at least one SN was identified (range, 1–3). In four cases, LM identified an SN deep at the base of the mesentery, requiring a more extensive resection. The tumor status of the SN correctly reflected the status of the entire specimen in all cases. In the only node-positive case of the nine laparoscopic cases, micrometastasis was found using the focused examination of a 2.8-cm moderately differentiated T3 sigmoid adenocarcinoma. In this case, the CK-IHC positive SN was the only positive lymph node of seven recovered in the specimen.

Ex Vivo Technique
Ex vivo LM was attempted in eight cases and was successful in seven cases (88%) (Table 2). Six of the seven cases were low rectal tumors whose drainage could not be mapped during OCR LM. Ex vivo LM identified at least one SN (range, 1–3) in five of the six cases.

SNs identified during ex vivo LM accurately reflected the nodal status in six of seven patients (86%) (Table 2). Interestingly, one of these patients had a low rectal carcinoma associated with SN micrometastases identified by CK-IHC. This SN was the only positive lymph node of the 16 harvested from the specimen. In two cases, the tumor was upstaged after identification of occult micrometastasis in an SN identified during ex vivo LM.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Published reports offer no consensus on the prognostic significance of nodal micrometastases in CRC. In a study of 46 patients initially reported as node-negative, re-examination using CK- and carcinoembryonic antigen (CEA)-IHC demonstrated evidence of micrometastases in 12 patients (26%). When compared with patients without evidence of nodal disease, however, there was no significant difference in 5-year survival.9 Similarly, Jeffers and associates10 detected CK-IHC micrometastases in 25% of 77 patients whose CRCs were initially staged as Duke’s B. Again, the presence of micrometastases had no significant effect on survival; however, random use of microsectioning for nodal specimens may have missed micrometastases. In fact, survival for true node-negative Duke’s B (stage II) disease could be better than now appreciated.

More recent studies have reported inferior survival in CRC patients with nodal micrometastases. Greenson and colleagues2 demonstrated an adverse effect on survival for micrometastatic disease missed by routine H&E staining but identified by CK-IHC. Similarly, Hayashi et al.11 demonstrated decreased survival in patients with p53 or K-ras mutations in colonic lymph nodes. In a study of Duke’s B CRC patients, Liefers and co-workers3 reported a 5-year survival rate of 50% for patients whose nodes expressed CEA, versus 91% for those whose nodes did not express CEA.

Multiple sectioning and IHC are too time-consuming and expensive for examination of all nodes in a CRC specimen; however, these ultrastaging techniques can be cost-effectively focused on the one to four nodes identified during LM. Unlike in melanoma4,12 and breast5,7,13 cancer, in which LM is used to avoid unnecessary radical lymphadenectomies, in CRC the LM technique is used to improve staging.6,7 The most straightforward approach to identifying the SNs draining a CRC is LM undertaken during OCR. In our study, OCR LM was successful in all but nine patients, six of whom had rectal tumors below the peritoneal reflection. Subsequent ex vivo LM in the six rectal specimens was successful in five cases.

It is unclear how blue dye is pushed through the lymphatics in the ex vivo specimen. Certainly the injection generates hydrostatic pressure, but there also may be a contribution from the pumping action of the myoendothelium of the lymphatics. Alternatively, surgical disruption may disrupt the neural pathways that regulate constriction of the lymphatics, thereby facilitating lymphatic flow. In any case, our initial findings indicated that ex vivo LM could successfully localize SN(s) de novo or after failure of in vivo LM. To confirm the accuracy of the ex vivo technique, we remapped the SNs in 10 operative specimens from patients who had undergone successful in vivo LM. In all cases, ex vivo injection of the dye intensified the staining of nodes identified during in vivo LM and did not stain any new nodes. Although we performed ex vivo LM on a back table in the operating room, it could also be undertaken in the pathology department. The ex vivo technique may therefore be a practical means for the pathologist to focus his or her analysis on SNs in CRC.

The appropriateness of LCR for malignancy is currently being studied in a randomized multicenter trial supported by the National Cancer Institute.14 To date, multiple American15–19 and international20–24 trials have demonstrated the safety and efficacy of LCR. In these studies, an average of 8 to 16 lymph nodes were harvested during LCR, which is about the same or slightly fewer than the number of nodes harvested during OCR. Because fewer nodes may be harvested at LCR, some question the oncologic soundness of the technique. In our experience, the average number of lymph nodes removed during LCR was 12, compared with 15 removed during OCR. It is unknown whether these larger resections have an oncological impact. Because we have largely limited LCR to small, early-stage tumors, only one of the nine patients had lymph node-positive disease (one CK-IHC positive SN draining a T3 lesion). However, if the ongoing multicenter trial proves LCR to be appropriate for more advanced cases, LM may become even more useful to outline all SNs, and their lymphatics for inclusion into the resection margins. Another advantage of LM during LCR is that colonoscopic injection tattoos the tumor with blue dye, precisely localizing the lesion. This was helpful because most of our patients had early-stage tumors and had undergone recent colonoscopic biopsies/polypectomies removing most if not all of the tumor. Therefore, these lesions were not usually visible or "palpable" laparoscopically.

Our successful application of LM for CRC6,7,25 is in part based on careful ongoing review of our failures to map at least one SN. In the present study, we were unable to identify an SN in three cases, two of which were low rectal tumors (operations performed before we began the ex vivo technique). In one of these cases, a locally advanced T4 tumor had grossly positive nodes (13 of 15 nodes positive on pathology). In such cases with grossly positive nodes, tumor replacement of the lymph node may inhibit the ability of the dye to traverse the lymphatics. This has been observed in melanoma and breast cancer. We do not recommend LM in such cases because analysis of SN status is unlikely to provide useful staging information.

Overall, extraperitoneal rectal tumors have proven to be quite problematic. Unlike intraperitoneal colon tumors, these tumors are not readily accessible and visible for injection upon exploration of the abdomen. Whether the dye injection was performed via sigmoidoscope with a spinal needle before mobilization of the rectum, or via the routine in vivo technique performed after rectal mobilization, visualization of the blue dye traveling in the lymphatic channels was more difficult and hence these were the most technically difficult cases in our series.

We have also analyzed cases in which the SN failed to reflect the tumor status of all nodes in the CRC specimen. In the present study, four cases had false-negative SNs. Each of these four failures occurred in locally advanced (T3 or T4) tumors: two right colon and two rectal tumors. It is not clear whether these failures reflected skip metastases. However, it is interesting to note that in three of the four false-negative cases, RT-PCR ultrastaging was positive for evidence of micrometastasis (unpublished data, 2000).

In conclusion, LM of the SNs draining primary CRC can be performed accurately by in vivo or ex vivo techniques. Focused examination of SNs demonstrates micrometastases missed by conventional techniques, upstaging almost one fifth of CRCs. Although the significance of nodal micrometastases found by ultrastaging techniques is currently unknown, a multicenter American College of Surgeons Oncology Group study (ACOSOG Z0170) is being designed to confirm the accuracy of LM and determine the prognostic significance of micrometastases in CRC. The ex vivo technique can be used successfully de novo or if in vivo LM is unsuccessful. LM at the time of LCR tattoos the primary tumor and outlines its primary lymphatic drainage.


   Acknowledgments
 
Supported in part by grant T32 CA 09689 from the National Cancer Institute and by funding from the Rogovin-Davidow Foundation, Los Angeles. The authors would like to thank Ms. Gwen Berry for her invaluable editorial support.


   Footnotes
 
Presented at the 53rd Annual Meeting of the Society of Surgical Oncology, New Orleans, Louisiana, March 16-19, 2000.

Received for publication March 17, 2000. Accepted for publication July 27, 2000.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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S. Saha, A. G. Dan, A. J. Bilchik, Y. Kitagawa, E. Schochet, S. Choudhri, L. T. Saha, D. Wiese, D. Morton, and M. Kitajima
Historical Review of Lymphatic Mapping in Gastrointestinal Malignancies
Ann. Surg. Oncol., March 1, 2004; 11(3_suppl): 245S - 249S.
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T.E. Le Voyer, E.R. Sigurdson, A.L. Hanlon, R.J. Mayer, J.S. Macdonald, P.J. Catalano, and D.G. Haller
Colon Cancer Survival Is Associated With Increasing Number of Lymph Nodes Analyzed: A Secondary Survey of Intergroup Trial INT-0089
J. Clin. Oncol., August 1, 2003; 21(15): 2912 - 2919.
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A. J. Bilchik, D. T. Nora, L. H. Sobin, R. R. Turner, S. Trocha, D. Krasne, and D. L. Morton
Effect of Lymphatic Mapping on the New Tumor-Node-Metastasis Classification for Colorectal Cancer
J. Clin. Oncol., February 15, 2003; 21(4): 668 - 672.
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R. J. Feezor, E. M. Copeland III, and S. N. Hochwald
Significance of Micrometastases in Colorectal Cancer
Ann. Surg. Oncol., December 1, 2002; 9(10): 944 - 953.
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A. J. Bilchik and D. T. Nora
Lymphatic Mapping of Nodal Micrometastasis in Colon Cancer: Putting the Cart Before the Horse?
Ann. Surg. Oncol., July 1, 2002; 9(6): 529 - 531.
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