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Originally published as Ann Surg Oncol Early Release 10.1245/ASO.2004.11.026 on July 12, 2004

Annals of Surgical Oncology 11:772-777 (2004)
© 2004 Society of Surgical Oncology
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ORIGINAL ARTICLES

Validation of Ex Vivo Lymphatic Mapping in Hematoxylin-Eosin Node-Negative Carcinoma of the Colon and Rectum

Jan H. Wong, MD, D. Scott Johnson, MD, Thomas Namiki, MD and Pamela Tauchi-Nishi, MD

From the Departments of Surgery (JHW, DSJ) and Pathology (TN, PT-N), John A. Burns School of Medicine, and the Prevention and Control Program (JHW), Cancer Research Center of Hawaii, University of Hawaii at Manoa, Honolulu, Hawaii.

Correspondence: Address correspondence and reprint requests to: Jan H. Wong, MD, Department of Surgery, John A. Burns School of Medicine, University of Hawaii at Manoa, 1356 Lusitana St., 6th Floor, Honolulu, HI 96813; Fax: 808-586-3022; E-mail: wongj{at}hawaii.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Substantial evidence supports that detailed analysis of the regional lymphatics will identify previously unrecognized micrometastatic disease in colorectal cancer. In order to determine whether the sentinel lymph node(s) (SLNs) harvested by ex vivo lymphatic mapping in node-negative colorectal cancer (CRC) are the most likely node(s) to harbor micrometastatic disease, we examined all nodes in CRC specimens in an identical fashion.

Methods: One hundred twenty-four specimens from patients with colorectal cancer were delivered to pathology in the fresh state and underwent ex vivo sentinel lymph node mapping. If negative by routine hematoxylin and eosin (H&E) analysis, the SLNs and non-SLNs were subjected to further analysis by level section H&E and immunohistochemical (IHC) analysis.

Results: A mean of 30 nodes were harvested (range, 5–111). Fifty-one patients (41%) were found to be node-positive by routine H&E analysis. SLNs were identified in all but three specimens. A total of 2177 nodes were analyzed from the 66 H&E node-negative specimens (1883 non-SLNs and 294 SLNs). Overall, metastases were identified in 13 of 278 SLNs and in only 5 of 1829 non-SLNs (P < .001). Only 5 of 66 patients (7.5%) had evidence of metastatic disease in non-SLNs when the SLNs were negative. Thirteen apparently node-negative patients (19.3%) were upstaged by IHC analysis of the SLNs (P = .04).

Conclusions: If the SLN is negative by both H&E and IHC analysis, the probability of finding metastases in a non-SLN is remote. If microstaging is demonstrated to be prognostically relevant, focused examination should be of the SLN(s).

Key Words: Colon cancer • Lymphatic mapping • Micrometastatic disease • Sentinel node


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Increasing evidence now supports the concept that when malignant tumors of epithelial tissues metastasize to the regional lymph nodes, they do so in a nonrandom fashion to the sentinel lymph node(s). A number of variations on the original selective lymphadenectomy technique1 have been developed to identify and harvest sentinel nodes in a number of solid tumor models. All, however, are based upon the fundamental principle of intraoperative mapping of the lymphatic drainage of the primary tumor to a sentinel node, in a manner similar to that which we originally described from a feline model.2 Despite the notable lack of standardization in the technical aspects of sentinel node dissection and biopsy, the vast majority of studies to date support the sentinel node hypothesis in all tumor systems examined.3

One of the potential advantages of sentinel node analysis is the ability to more thoroughly analyze a small volume of tissue in a cost- and time-efficient manner. Routine examination by hematoxylin-eosin (H&E) staining of the regional lymph nodes involves only a small fraction of the total tissue submitted for examination and may understage a substantial number of individuals.4 The observation that when metastatic disease is present in the regional lymphatics it most commonly is in the blue-stained and/or hot node suggests that these techniques indeed identify lymph nodes that are most likely to harbor metastatic disease. However, the improvement in staging accuracy by sentinel node harvesting may be due in part to more thoroughly analyzed node(s) rather than just the result of mapping of the primary lymphatic drainage. For this reason, validation of the sentinel node hypothesis requires that nonsentinel nodes be examined in as nearly identical a fashion as blue-stained and/or hot nodes identified by lymphatic mapping.

In contrast to breast cancer and melanoma, for which formal node dissections in sentinel node–negative patients have largely been abandoned,5 sentinel node mapping in colon cancer routinely involves resection of the mesentery of the regional lymphatics and provides the opportunity to perform confirmatory studies on nonsentinel nodes. We have previously described a novel technique of lymphatic mapping of resected colorectal cancer specimens.6 This report examines whether blue nodes identified by ex vivo lymphatic mapping in node-negative colorectal cancer patients are the most likely to harbor occult metastatic disease.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Technique of Ex Vivo Lymphatic Mapping
The study was conducted following institutional review board approval. The technical details of ex vivo lymphatic mapping have been previously described in detail.6 In brief, after gross examination, the fresh colon was incised longitudinally on the antimesenteric border and in the case of rectal tumors on the anterior border opposite the mesorectum. In opening the colon or rectum, no attempt was made to avoid the tumor if it involved the antimesenteric wall of the colon. Utilizing a tuberculin syringe, we administered four separate submucosal injections of approximately 0.125 cc of isosulfan blue (Lymphazurin 1% in aqueous solution; Ben Venue Laboratories, Bedford, OH) in four quadrants around the tumor (Fig. 1A). The injections were administered at the proximal and distal margins of the tumor along the longitudinal axis of the specimen and at 90° from these injection sites. If the tumor extended to the antimesenteric segment of colon, an injection was administered on both sides of the divided tumor. A submucosal wheal of approximately 1 cm was obtained. The injection sites were then gently massaged for approximately 2 to 5 minutes.



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  		FIG. 1. Ex vivo lymphatic mapping utilizing isosulfan blue. A, a 1-cm submucosal wheal utilizing approximately 0.1 mL of isosulfan blue is created, and the injection site is gently massaged; B, blue-stained nodes are harvested.

 
The mesentery was then examined by gently incising the overlying peritoneum at the base of the palpable tumor and at the junction of the mesentery with the colon. The mesenteric fat was bluntly separated, and with meticulous blunt dissection, blue lymphatic channels were identified and subsequently traced through the adipose tissue of the mesentery to a blue-stained lymph node (Fig. 1B). These blue-stained lymph nodes were then individually harvested and submitted for histologic examination.

The remainder of the resected specimen was then fixed in formalin overnight, prior to further examination. Lymph nodes were harvested as follows: the peritoneum overlying the remainder of the mesentery was incised and then examined by careful palpation for the presence of lymph nodes. Any firm tissue remaining after gentle pressure on the mesenteric fat was isolated from the surrounding mesenteric fat and sent as a lymph node specimen for histologic examination by routine H&E staining.

Pathologic Examination
All lymph nodes larger than 3 mm were bivalved in the longitudinal axis and embedded in paraffin. Lymph nodes smaller than 3 mm in diameter were embedded whole. A single section was routinely performed (two faces in bivalved lymph nodes and a single face in lymph nodes <3 mm in diameter). Histologic sections were processed in the usual manner: cut at 4 µ and stained with H&E. When the node basin was determined to have metastatic disease by routine H&E staining, no further analysis was performed. However, when the node basin was determined to be histologically negative by routine H&E, then all lymph nodes were further analyzed.

Additional level sections of paraffin-embedded lymph nodes were obtained at 300 µ. A single section was obtained after the first additional level and stained with antibodies directed at low- and high-molecular-weight cytokeratin (Pan-Keratin AE1/3, CAM 5.2, 35bH11, prediluted; Vantana Medical Systems, Tucson, AZ). Immunostaining was performed with avidin-biotin peroxidase with use of the BioTek Automated Staining System (Vantana Medical Systems). Formalin-fixed paraffin-embedded sections of tonsils were used as positive controls, and a section from each block was taken and incubated with negative control buffer. Positive nodes were defined as having glandular elements present on deeper sections by either H&E staining or immunostaining or clusters of immunostain-positive cells. A single immunostain-positive cell was not considered positive for metastatic disease.

Statistical Analysis
The Mantel-Haenszel test was used to compare the H&E and cytokeratin IHC results for sentinel and nonsentinel lymph nodes, with use of the NCSS Statistical System for Windows (NCSS, Kaysville, UT).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient and Primary Tumor Characteristics
One hundred twenty-four patients with carcinoma of the colon and rectum were studied. Characteristics of the patients and primary tumors are detailed in Table 1. All rectal cancer patients whose specimens were delivered fresh to pathology were included in the study population. It has become increasingly common to treat these patients preoperatively with 5-fluorouracil-based chemotherapy and radiation. The patients ranged in age from 29 to 92 years, with a mean age of 64.3 years. The majority of patients were male. The vast majority of patients (75%) had transmural extension of the primary tumor (Fig. 2).


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  		TABLE 1. Patients and primary tumor characteristics
 


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  		FIG. 2. Distribution of primary tumors of the colon and rectum. The majority of tumors are transmural lesions.

 
Sentinel and Nonsentinel Node Data
A total of 3726 nodes were harvested from 124 patients. The mean number of nodes examined in all specimens was 30 (range, 5 to 111). Blue nodes were identified in all but four patients (96.7%). Four hundred sixty-five blue, presumably sentinel, nodes were identified. The mean number of blue nodes identified was 3.8 (range, 0 to 21). Fifty-one patients (41.1%) were identified as node-positive on routine pathologic examination by H&E staining alone. Twenty-seven sentinel nodes from these 51 patients were positive for metastatic disease (sensitivity, 54%) by routine H&E staining. The remaining patients with tumor-negative regional lymph nodes were the focus of further study, as described in the Materials and Methods section.

Table 2 summarizes the results of further analysis of the node-negative individuals. A total of 2177 nodes were harvested from these H&E-node-negative individuals (mean, 29.4 nodes), of which 294 were blue-stained sentinel nodes. A mean of 3.9 sentinel nodes (range, 0–21) were harvested from these node-negative individuals. An apparently high number of blue-stained nodes in two patients was the result of extravasations of isosulfan at the time of injection, early on in the development of the technique. Of the 294 sentinel nodes identified in H&E-negative specimens, 2 were positive for metastatic tumor by H&E staining and 11 others were positive by IHC analysis. The identification of occult tumor occurred in 4.4% of these sentinel nodes. Eighteen percent of 66 patients were upstaged by this procedure.


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  		TABLE 2. Results of level sectioning and cytokeratin immunohistochemistry in nodes that were metastases free by routine H&E examination
 
Among the 1883 nonsentinel nodes harvested from these 66 H&E-node-negative individuals, H&E demonstrated that 3 were apparently nonsentinel nodes with metastases, and 2 were positive by IHC analysis when the sentinel nodes had no IHC-evident metastatic disease (P < .0001 by Mantel-Haenszel test). Of the 66 patients node-negative patients, 13 (19.5%) were upstaged by level sectioning and IHC staining of the blue nodes, and only 5 were upstaged by level sectioning and IHC analysis of nonblue nodes (P = .04 by Mantel-Haenszel test).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The presence or absence of nodal metastases in colorectal carcinoma is the single most important prognostic factor in apparently localized disease. Patients who are free of nodal metastases generally can anticipate an excellent chance of survival. In contrast, the presence of regional node metastases substantially increases the risk of developing recurrent disease and currently defines patients who are candidates for adjuvant systemic therapy.7 For this reason, careful assessment of the regional lymphatics is routinely recommended. Inadequate identification and/or harvesting of regional nodes in colorectal cancer can impact outcome.8,9

In an effort to minimize the potential for inaccurate staging of the regional lymphatics in carcinoma of the colon and rectum, a number of strategies have been employed. These include more thorough dissection of the regional lymphatics by techniques such as fat clearance,10 as well as a more thorough analysis of those nodes identified either by IHC analysis or reverse transcriptase polymerase chain reaction technology.11–13 All of these approaches can be labor-intensive, cumbersome, and costly. This report examines the value of ex vivo lymphatic mapping of carcinoma of the colon and rectum in staging patients who are node-negative by routine H&E analysis. Our results demonstrate that blue-stained nodes in H&E-node-negative patients with colorectal cancer are far more likely to contain metastatic disease than non-blue-stained nodes and represent true sentinel nodes.

The value of accurate staging of cancer patients is well recognized. Classification and staging of cancer allow information to be readily communicated to others, assist in the development of clinical recommendations regarding treatment, and provide a mechanism for comparing groups of individuals and the outcomes of treatments. The ability to identify nodal involvement by metastatic disease is directly related to the extent of regional lymphadenectomy and the methods of pathologic examination.14 In an effort to ensure accurate staging in colorectal cancer, a minimum number of nodes that need to be harvested and/or examined has been recommended.14–17 Current recommendations from the American Joint Committee on Cancer are for a minimum of 12 nodes to be examined for accurate staging of colorectal cancer.18 However, it is well recognized that nodal harvesting and/or examination may be highly variable. One approach that is being investigated to improve staging is lymphatic mapping to identify the sentinel node(s).

The sentinel node is the first draining lymph node or nodes on the direct lymphatic drainage pathway from the primary tumor site. For this reason, it has been hypothesized that the sentinel nodes are the most likely to receive metastases from the primary tumor.1 Substantial evidence now supports the sentinel node hypothesis in melanoma and breast cancer. For this reason, the technique of sentinel node dissection is steadily gaining popularity as a means of improved staging for individuals with several tumor types, including carcinoma of the colon and rectum. Although a number of fundamental principles have evolved in lymphatic mapping, a uniform implementation of this procedure in any tumor type has yet to be adopted. Although the terms are frequently utilized interchangeably, the operative identification of a "blue" or "hot" node does not necessarily imply a biologic sentinel node. This can be attested to by the variable false-negative rates reported for breast cancer19 and colorectal cancer.20

Two general approaches to identifying sentinel nodes in colon cancer have been utilized. The intraoperative technique21 employs a subserosal injection of isosulfan blue and intraoperative lymphatic mapping. Blue-stained nodes are marked prior to the completion of a formal colectomy. This approach has the advantage of encompassing aberrant lymphatic drainage but may violate mesenteric fascial planes and possibly increase the risk of local recurrence22 and is not feasible in rectal cancer. Furthermore, the subserosal injection of isosulfan blue may make it impossible to identify pericolic nodes that may be adjacent to the injection site and places the patient at risk for adverse reactions that have been associated with the intraoperative use of isosulfan blue.23

Ex vivo lymphatic mapping has the potential advantage of precise introduction of isosulfan blue into the submucosa, the site where lymphatics from the mucosa coalesce prior to penetrating the muscularis propria to drain to the regional nodes and presumably the site where tumor cells initially gain access to the lymphatic system. Gentle massaging induces lymphatic flow, and the ex vivo technique avoids the potential for adverse reactions that have been reported with increasing frequency when isosulfan blue has been utilized in vivo23 and can be performed in all sites of the colon and rectum. Finally, ex vivo lymphatic mapping has the potential advantage that all specimens, when delivered in the fresh state to pathology, can be examined and mapped in a more uniform fashion than when studied by multiple surgeons and may potentially shorten any learning curves associated with this procedure.

Our initial studies of ex vivo sentinel node mapping in colon and rectal cancer6 suggested that the sensitivity of ex vivo lymphatic mapping in colorectal cancer with H&E staining of a single section was only 58.3%. This has remained essentially unchanged with increasing experience. However, the sensitivity of ex vivo lymphatic mapping improved substantially with the addition of IHC staining (to 93.7%). In contrast to cutaneous melanoma and breast cancer, in which the status of the sentinel node guides surgical treatment,1,5 the opportunity to routinely process the entire regional node basin in a standard fashion negates the clinical relevance of a false-negative lymphatic mapping in colorectal cancer because these individuals would be anticipated to be identified by routine pathologic examination and no additional relevant clinical information is gained by IHC analysis. For this reason, we did not attempt to establish the sensitivity of this technique in H&E-node-positive individuals. However, whether or not a more thorough analysis of blue nodes improves staging for apparently node-negative individuals is of considerable interest and is potentially clinically relevant.

Some investigators have questioned whether improved staging following lymphatic mapping, rather than being due to the biologic significance of the sentinel node, is the result of a more thorough histopathologic analysis of blue-stained nodes.24 In order to address this concern, we examined all nodes harvested with identical histopathologic techniques. Our results demonstrate that if metastatic disease is identified with the more sensitive technique of level sectioning and IHC analysis, it is far more likely to be identified in blue-stained nodes.

As in all experiences with sentinel node staging, there is a definable false-negative rate. The reasons for this remain unclear. An even more thorough analysis of sentinel nodes has identified disease that was not originally identified with routine IHC processing,25 suggesting micrometastatic deposits of disease can still be missed. Others26 have suggested that metastatic tumor cells may enter a compartment of the lymph node that may not be examined even with level sectioning. However, in contrast to melanoma and breast cancer, in which the results of sentinel node staging are currently used to define the surgical management of the regional lymphatic basin, a formal lymphadenectomy remains a standard component of a cancer operation for carcinoma of the colon and rectum, and ex vivo lymphatic mapping serves only to lower the false-negative rate of routine H&E analysis.

The clinical relevance of upstaging colorectal cancer with more sensitive assays is controversial. Although patients who are node-negative generally enjoy excellent survival prospects, a significant number of individuals do have recurrences and die of metastatic disease. It is postulated that this is partly due to understaging. Some have suggested that the identification of tumor cells by IHC analysis12 or even antigen-specific nested reverse-transcriptase polymerase chain reaction13 has prognostic significance. However, others have been unable to demonstrate that restaging based upon the identification of micrometastatic deposits in lymph nodes impacts prognosis.11,27,28 We have demonstrated that micrometastatic disease (<2 mm in diameter) in lymph nodes that has been identified by routine H&E staining in colorectal cancer patients has the same prognostic impact as macrometastatic disease (≥2 mm in diameter),29 and this suggests that more sensitive assays detect prognostically relevant disease. However, this issue remains to be resolved in large prospective trials.

This report demonstrates that the technique of ex vivo lymphatic mapping that we described for carcinoma of the colon and rectum is technically feasible and identifies nodes in the regional lymphatics that are biologic sentinel nodes. These sentinel nodes are the most likely to harbor occult metastatic disease in apparently node-negative colorectal cancer patients. If these findings were demonstrated to be prognostically relevant, then the most cost-effective means of further staging for H&E-node-negative patients would be a focused examination of the sentinel nodes.


   ACKNOWLEDGMENTS
 
Supported in part by a grant from the Hawaii Community Foundation and the Surgical Oncology Research Fund at the University of Hawaii Foundation.

The acknowledgments are available online in the fulltext version at www.annalssurgicaloncology.org. They are not available in the PDF version.


   FOOTNOTES
 
Ex vivo lymphatic mapping of node-negative colorectal cancer specimens and immunohistochemical analysis of all nodes demonstrated that micrometastatic disease was far more likely to be present in sentinel nodes than in nonsentinel nodes.

Received for publication November 17, 2003. Accepted for publication April 14, 2003.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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  23. Leong SPL, Donegan E, Heffernon W, et al. Adverse reactions to isosulfan blue during selective sentinel lymph node dissection in melanoma. Ann Surg Oncol 2000; 7: 361–6.[Abstract/Free Full Text]
  24. Turner RR, Ollila DW, Krasne DL, Giuliano AE. Histopathologic validation of the sentinel lymph node hypothesis for breast carcinoma. Ann Surg 1997; 226: 271–8.[CrossRef][Medline]
  25. Gershenwald JE, Colome MI, Lee JE, et al. Patterns of recurrence following a negative sentinel lymph node biopsy in 243 patients with stage I or II melanoma. J Clin Oncol 1998; 16: 2253–60.[Abstract]
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