| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
SUPPLEMENT |
From the Departments of Surgery, Michigan State University and McLaren Regional Medical Center (SS, AGD, ES, SC, LTS, DW), Flint, Michigan; John Wayne Cancer Institute (AJB, DM), Santa Monica, California; and Keio University School of Medicine (YK, MK), Tokyo, Japan.
Correspondence: Address correspondence and reprint requests to: Sukamal Saha, MD, FACS, FRCS, Department of Surgery, McLaren Regional Medical Center, Michigan State University, 3500 Calkins Road, Suite A, Flint, MI 48532; Fax: 810-230-9607; E-mail: ssahadr{at}aol.com
ABSTRACT
The advent of sentinel lymph node mapping (SLNM) has had a profound impact on the surgical management of breast cancer and melanoma over the past decade. However, SLNM in gastrointestinal malignancies is still in its infancy. The role of SLNM in gastrointestinal malignancies is to increase staging accuracy and to reduce the understaging associated with standard surgical and pathological techniques. Numerous authors have described the successful use of SLNM in colon, rectal, gastric, esophageal, and anal canal malignancies, with a high degree of accuracy and upstaging by detailed pathological analysis of the sentinel nodes. Over the past 2 years, research and publications related to gastrointestinal lymphatic mapping have dramatically increased worldwide.
Key Words: Gastrointestinal malignancies • History • Sentinel node • Lymph mapping
The routine identification and removal of regional lymph nodes in solid neoplasms is essential for accurate staging, assessment of prognosis, and determination of adjuvant therapies. For more than 100 years, radical lymphadenectomy has been the diagnostic and therapeutic gold standard for the management of metastatic nodal disease, despite well-known morbidities such as lymphedema and nerve damage. Over the past 2 decades, advances in screening modalities and technology have increased the frequency of detection of solid tumors at earlier stages of disease. Today, more than 50% of patients with breast cancer and malignant melanoma present with American Joint Commission on Cancer (AJCC) stages I and II disease (without nodal metastases). The majority of patients without nodal metastases do not benefit from complete removal of the regional lymph nodes, a fact challenging radical lymphadenectomy as a standard of surgical management. Sentinel lymph node mapping (SLNM) has been developed as a modality for accurate nodal staging of solid tumors, which spares many patients the morbidities associated with radical lymphadenectomy when the sentinel lymph node is negative for metastasis.
As early as the sixth century, Actius and Amida documented the involvement of the lymphatic system in the spread of cancer cells from breast tumors.1 Over the centuries, several physicians and anatomists developed the theories of lymphatic dissemination of cancer cells leading to our current understanding of lymphatic metastases. In 1950, Weinberg and Greaney2 first reported direct visualization of lymphatic channels with the use of pontine sky-blue dye in gastric cancer. Similarly, Morl3 in 1952 revealed the lymphatic drainage pattern of the breast to the axilla using India ink. The lymphoscintigraphy technique, which was developed during the 20th century, has also facilitated study of the lymphatics. In the early 1950s radioisotope-labeled agents were introduced as tracers for lymphatic mapping. Sherman and Ter-Pogossian4 in 1953 used radioactive gold colloid to localize regional lymph nodes intraoperatively. Refinement of the lymphoscintigraphy technique continued over the decades with the experimental use of various radioactive substances. Ultimately, technetium sulfur colloid emerged as the radioactive tracer of choice in North America and Europe.
The 1960s brought the first description of the sentinel node. Gould and colleagues5 are credited with coining the term sentinel node in 1960. In 1970, Kett and colleagues6 described the sorgius node as the first node to receive drainage from the breast. In 1977, Cabanas7 first described the physiologic importance of this node in his study of penile cancer. He postulated that if the first draining node, the sentinel lymph node, was negative for metastasis, the remaining lymph nodes in the nodal basin may be spared.
However, the true value of the sentinel lymph node became evident only after the pioneering work of Morton and colleagues8 in the management of malignant melanoma. More than 25 years ago, Morton’s group first used radioactive gold colloid to identify the regional lymph node basin that drained truncal melanomas.9,10 They described the use of cutaneous lymphoscintigraphy to identify the lymph basins at risk for metastasis from truncal primary melanomas, and they introduced selective lymphadenectomy of the deep iliac/obturator lymph nodes directed by the pathologic status of Cloquet’s node and the superficial inguinal nodes.11 Morton proved that the sentinel lymph node could predict the status of the nodal basin with 99% accuracy. Hence, patients with early-stage melanoma and negative sentinel nodes could be spared the morbidity associated with a regional lymph node dissection.
Published reports by Krag et al.12 and Giuliano et al.13 in the early 1990s pioneered the use of SLNM for breast tumors with similar success. Over the next decade SLNM was utilized for accurate staging of various solid tumors, including colorectal cancer (1997),14 Merkel cell cancer (1997),15 thyroid cancer (1998),16 vulvar cancer (1998),17 prostate cancer (1999),18 lung cancer (1999),19 gastric and esophageal cancer (2000),20 and anal canal cancer (2001).21 The reliability of the mapping technique in identifying the sentinel node with use of blue dye and/or radioactive tracer became well established by the late 1990s for the management of breast cancer and melanoma. During this period, it also became evident that focused analysis of these sentinel nodes with multilevel sections and immunohistochemistry resulted in the upstaging of a significant percentage of cancers, whose metastasis would otherwise have been undetected by conventional pathological means.
Colorectal cancer remains the third most common malignancy in the United States, causing more than 50,000 deaths per year. More than 50% of patients with colorectal cancer are diagnosed initially with AJCC stage I and II disease. About 15% to 25% of these patients develop regional or distant metastases within 5 years of the diagnosis, in spite of a presumably curative operation. This is likely due to pathological understaging from missed micrometastasis in lymph nodes, which are often less than 5 mm in size.22,23 Hence mapping and focused pathological analysis of the sentinel node could be useful in the upstaging of colorectal cancer. Whereas SLNM can reduce the extent of regional lymph node dissection in breast cancer and melanoma, the primary purpose of SLNM in colorectal cancer is to upstage tumors whose metastasis would remain undetected by conventional pathological means. The accurate staging of colorectal cancer is highly dependent upon the number of lymph nodes harvested and examined by the pathologist.24,25 Recently developed pathological techniques are highly sensitive for identifying micrometastatic disease in lymph nodes, but it is cost-prohibitive and highly impractical to ultrastage all the nodes in a given specimen.26 It was therefore hypothesized that focused analysis of the sentinel node could represent an accurate, time-efficient, and cost-effective means of reducing the understaging associated with conventional pathological examination.
The first report of SLNM in colorectal cancer was a feasibility study presented in 1997 at the Society of Surgical Oncology’s 50th Annual Cancer Symposium in Chicago.14 This series of 10 patients was followed by a series of 56 patients presented at the 17th International Cancer Congress in Brazil in 1998.27 This report confirmed the high (98%) feasibility of the technique and demonstrated its high (95%) degree of accuracy for predicting the status of the nodal basin. In 1999, Joosten et al.28 in the Netherlands published a report of SLNM in 50 patients with colorectal cancer. On the basis of a feasibility rate of 70% and a false-negative rate of 60%, they concluded that SLNM was not a reliable method of staging colorectal cancer. However, their injection method and especially the timing of pathological examination differed from those described by us. Their results underscore the importance of adhering to strict technical details of the procedure and following a specific protocol for handling and processing of the specimen by the pathologist. A subsequent publication in the Annals of Surgical Oncology29 outlined the technical details associated with excellent feasibility (99%) and accuracy (96%) rates as reported in our original studies.
Later that year, Tsioulias and Bilchik30 at the John Wayne Cancer Institute reported lymphatic mapping in a series of 65 patients with gastrointestinal neoplasms of the colon, small bowel, stomach, and pancreas. Lymphatic mapping was successful in 95% of their patients. Of the 36 patients with nodal disease, 32 (89%) had sentinel nodes positive for metastases and 11 cases were upstaged by the detection of micrometastatic disease in the sentinel node with immunohistochemistry or multilevel sections. This study further confirmed the validity of SLNM in colorectal cancer.
In December 2000, the sentinel node issue of the Surgical Clinics of North America provided a collective overview of SLNM in gastrointestinal neoplasms. A review by Saha et al.31 included coauthor Wong’s technique of ex vivo lymphatic mapping in colorectal cancer. Kitagawa’s group20 focused on the use of SLNM in esophageal, gastric, and colorectal cancers and for the first time described the use of radiolabeled tracers and a hand-held gamma probe for successful lymphatic mapping in colorectal cancer. Thorn32 in 2000 and Merrie et al.33 in 2001 combined blue dye and radioactive tracer for mapping, as previously described in breast and melanoma. The success rates of dual-agent mapping were 100%32 and 88%.33 In 2001, Wood et al.34 reported a series of 75 patients who underwent lymphatic mapping by in vivo, ex vivo and laparoscopic techniques.34 The overall success rate of mapping was 96%, and the rate of occult micrometastasis was 17%.
The first large series of ex vivo SLNM in colon and rectal cancers was published by Wong et al.35 in 2001. Laparoscopic SLNM has been attempted at a few centers for colorectal and gastric cancers, with high success rates34,36 comparable to those associated with mapping performed during open laparotomy. Also in 2001, Bilchik et al.37 first reported molecular profiling of colon cancer with use of the RT-PCR technique for multiple markers in 40 patients. This study showed a high correlation between the expression of p53, beta-HCG, c-Met, and uMAGE in a primary tumor and the presence of micrometastases in regional lymph nodes. A collaborative study between Michigan State University and the John Wayne Cancer Institute in 2001 revealed a 98% rate of successful mapping in 203 patients; occult metastases were detected in 14% of patients.38 In 2002, researchers at multiple institutions reported successful mapping with high accuracy rates, thus further validating the use of this technique in the management of colorectal cancer.39,40,41
TRACERS
Isosulfan blue (Lymphazurin 1%; US Surgical, Norwalk, CT) has been the dye of choice for SLNM in melanoma and breast cancer. Similarly, isosulfan blue was found to be highly effective for mapping colorectal cancer, as used by us and others in North America. Patent Blue V dye (Rhone-Poulenc, Fauldings, Adelaide, Australia) has been successfully used by researchers in Europe and Japan.28,32,42 In Japan, the most commonly used tracer for lymphatic mapping is technetium-99m Sn (tin) colloid, as initially reported by Kitagawa et al.20 In contrast, the most commonly used radioactive tracer in North America is technetium-99m sulfur colloid. Although rare, the adverse reactions associated with isosulfan blue have prompted the investigational use of a 10% solution of fluorescein (Alcon Labs, Fort Worth, TX) for lymphatic mapping in colorectal cancer, as first described by Dan et al.43 in 2002. This study reported success rates of 96% for fluorescein versus 99% for isosulfan blue and accuracy rates of 89% and 95%, respectively. Fluorescein was a safe alternative and was especially useful for visualization of fluorescent sentinel nodes in a darkened room with Wood’s light, for patients with thick mesenteries.
OTHER GASTROINTESTINAL TUMORS
Because of the high prevalence of gastric and esophageal cancers in Asia, sentinel node mapping for these tumors was pioneered in Japan. Kitagawa et al.20 were the first to report successful lymphatic mapping of gastric and esophageal tumors in 2000. The application of this technique, especially in early gastric cancer as seen in Japan, has led to the use of sleeve resection with selective lymphadenectomy in sentinel node-negative patients. This has drastically altered the paradigm of gastric cancer surgery from radical lymphadenectomy to minimally invasive gastric surgery. Lymphatic mapping has also been attempted to a limited degree in pancreas and small-bowel tumors,30 as well as in tumors of the liver44 and anal canal.21
ABERRANT DRAINAGE
Unlike SLNM for breast cancer and melanoma, SLNM for colorectal cancer emphasizes accurate staging rather than changing the extent of lymphadenectomy. In colorectal cancer, standard oncologic resection is recommended irrespective of the status of the sentinel nodes. Occasionally, however, aberrant lymphatic drainage is seen beyond the normal resection margins. This aberrant pattern is observed in up to 8% of patients with colorectal tumors, in whom the margin of resection is extended beyond conventional surgery.45 Such aberrant drainage was also observed in patients with other gastrointestinal malignancies.46
PATHOLOGY OF SENTINEL LYMPH NODES
Focused examination of sentinel nodes allows the pathologist to diagnose micrometastases that would have been missed by conventional histological evaluation. In 2000, the first published series on the pathologic evaluation of sentinel nodes versus nonsentinel nodes was by Wiese et al.26 Lymph node metastases were detected in 45% of the 82 patients. These metastases were detected in 25% of 152 sentinel nodes as opposed to 5.4% of 1123 nonsentinel lymph nodes. Multilevel serial sections only in the sentinel lymph nodes improved detection of micrometastases. Serial multilevel sections of 330 initially negative nonsentinel nodes in the first 25 consecutive patients yielded only a 0.6% rate of additional positive nodes. This further confirms the benefit of ultrastaging only the sentinel lymph nodes, as opposed to all the nodes recovered from the specimen.
INTERNATIONAL SENTINEL NODE CONGRESSES
The rapid development of the sentinel node mapping technique for solid tumors across the world led to the establishment of the International Sentinel Node Congress. The Second International Congress, held in Santa Monica, California, in 2000, was the first major venue for this evolving field in gastrointestinal malignancies. At the Congress, only four papers were presented on the topic of gastrointestinal SLNM.36,38,45,47 Just 2 years later, at the Third International Sentinel Node Congress, held in Yokohama, Japan, there was a dramatic increase in the number of presentations related to gastrointestinal tumors, including 78 papers representing research on esophageal (n = 14), gastric (n = 41), colorectal (n = 21), and anal canal (n = 2) cancers, from 10 different countries. This further emphasizes the utility of lymphatic mapping for accurate staging of colorectal and other gastrointestinal tumors.
FUTURE DIRECTIONS
Various molecular markers are currently being developed as prognostic factors in gastrointestinal malignancies. In the future, the correlation of such factors to the sentinel node status will markedly increase our understanding of the biologic properties unique to the sentinel lymph nodes.
The prognostic implications of micrometastases in gastrointestinal malignancies have been debated.48,49 As yet, there are no data regarding prognostic significance of sentinel lymph node status in gastrointestinal malignancies. Validation of this mapping technique in colorectal cancer by a multicenter trial has been proposed by the American College of Surgeons’ Oncology Group (ACOSOG). Further trials evaluating the prognostic parameters of the primary tumors with the sentinel lymph node status may allow us to identify those patients who truly would have risk factors for distant disease. In our opinion, further studies of this mapping technique may also identify those patients whose disease is truly localized (node-negative by immunohistochemistry and reverse-transcriptase polymerase chain reaction assay) and thus can be cured by adequate oncologic resection without adjuvant therapy.
ACKNOWLEDGMENTS
The authors acknowledge the following individuals for their generous support in the preparation of the manuscript: Cynthia Duncanson, Maureen Snyder, Diane Gardner, and Dr. Kim Barber.
The acknowledgments are available online in the fulltext version at www.annalssurgicaloncology.org. They are not available in the PDF version.
FOOTNOTES
Presented at the Third International Sentinel Node Congress, Yokohama, Japan, November 16–18, 2002.
Presented at the 3rd International Congress on Sentinel Lymph Node Mapping in Yokohama, Japan, November 2002.
The advent of sentinel lymph node mapping (SLNM) has increased staging accuracy and reduced the understaging associated with standard surgical and pathological techniques. Over the past 2 years, research and publications related to gastrointestinal lymphatic mapping have dramatically increased worldwide.
Received for publication December 9, 2003. Accepted for publication January 16, 2004.
REFERENCES
This article has been cited by other articles:
 |
|
 |
|
  R. J. de Haas, D. A. Wicherts, M. G. G. Hobbelink, I. H. M. B. Rinkes, M. E. I. Schipper, J.-A. van der Zee, and R. van Hillegersberg Sentinel Lymph Node Mapping in Colon Cancer: Current Status Ann. Surg. Oncol., March 1, 2007; 14(3): 1070 - 1080. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
