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The Oncologist, Vol. 8, No. 1, 59–68, February 2003
© 2003 AlphaMed Press

ORIGINAL PAPER
IMAGING AND DIAGNOSTICS

Current Status of Sentinel Lymph Node Mapping and Biopsy: Facts and Controversies

James W. Jakub, Solange Pendas, Douglas S. Reintgen

The Lakeland Regional Cancer Center, Lakeland, Florida, USA

Correspondence: James W. Jakub, M.D., Lakeland Regional Cancer Center, 300 Parkview Place, Lakeland, Florida 33804, USA. Telephone: 863-603-6565; Fax: 863-603-6576; e-mail: jim.jakub{at}lrmc.com


   LEARNING OBJECTIVES
Top
 Learning Objectives
Abstract
 Introduction
 Melanoma
 Breast
 Colon
 Conclusion
 References
 General References
 
After completing this course, the reader will be able to:

  1. Explain the current application of lymphatic mapping and sentinel lymph node biopsy.
  2. Discuss the ability of sentinel lymph node biopsy to allow a more focused pathologic evaluation and identify tumor cells not previously detected by standard techniques.
  3. Discuss the major controversies of lymphatic mapping and sentinel lymph node biopsy as they apply to melanoma, breast cancer, and colon cancer.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 Melanoma
 Breast
 Colon
 Conclusion
 References
 General References
 
Lymphatic mapping and sentinel lymph node biopsy were first reported in 1977 by Cabanas for penile cancer. Since that time, the technique has become rapidly assimilated into clinical practice. Morton first described the application of lymphatic mapping for melanoma only a decade ago, and this technique is now accepted as the standard of care. The application for lymphatic mapping and sentinel lymph node biopsy in breast cancer remains approximately 5 years behind its utilization in melanoma. This technique has the potential to be utilized in all solid tumors. The rapid assent of this technique in clinical practice is the result of multiple factors, including accuracy, decreased morbidity, and supplying the pathologist with only a few nodes to allow a more focused and sensitive pathologic evaluation. Despite the success and acceptance of lymphatic mapping, many controversies remain. We have attempted to clearly highlight these controversies in this review.

Key Words. Lymphatic mapping • Sentinel lymph node biopsy • Breast cancer • Melanoma • Colon cancer


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Melanoma
 Breast
 Colon
 Conclusion
 References
 General References
 
The sentinel lymph node (SLN) is defined as the first node in the lymphatic basin into which the primary tumor drains. The primary afferent lymphatic first drains into the SLN of the respective basin. Therefore, the status of the SLN(s) accurately reflects the entire basin. If the SLN is not involved with metastatic disease, the remainder of the lymph nodes should also be negative. Likewise, if the SLN is positive, the risk exists that higher order nodes may also be involved with metastatic disease.

Classic anatomic dermal guidelines of lymphatic drainage arose from work in the late 1800s by Sappey, who injected mercury into cadavers. His 1874 study illustrated lines of demarcation across the midline transversely and horizontally along an imaginary line at the umbilicus connecting to the L2 area on the back. Lesions above "Sappey’s line" were thought to drain to the ipsilateral axilla and skin sites below Sappey’s line to the ipsilateral groin. Watershed areas, sites of unpredictable drainage, were felt to be limited to 2.5 cm on each side of Sappey’s line or the midline [1]. The predictability of this drainage pattern has since been refuted utilizing lymphoscintigraphy, a nuclear medicine study. The physician cannot accurately predict the nodal basin unless the dermal tumor lies on an extremity. Even in this situation, in-transit nodes might be missed in the epitrochlear and popliteal spaces in 5% of the population [2]. This finding casts significant concern on the four original randomized trials evaluating the efficacy of elective lymph node dissection (ELND) versus observation for intermediate thickness melanomas. It is estimated that one-third of the patients in the ELND arms had the incorrect nodal basin dissected [3-5].

The procedure relies on the concept of the SLN, which Cabanas first described when he used lymphangiograms performed via the dorsal lymphatics of the penis to demonstrate the existence of specific ‘lymph node centers’ that predicted the nodal status of a penile tumor [6]. In 1992, Morton and colleagues described lymphatic mapping utilizing an intradermal isosulfan blue dye injection technique for malignant melanoma and were the first to employ this concept to localize SLNs in patients with malignant melanoma [7]. The authors demonstrated a high success rate in identifying an SLN and in achieving low false-negative rate. This technique was reproduced at other institutions demonstrating similar findings. Later, Giuliano applied intraparenchymal blue dye lymphatic mapping to the nodal evaluation of breast cancer [8]. Development of the hand-held gamma radiation detectors led Krag to investigate the use of intraparenchymal Tc99m sulfur colloid as a mapping agent to localize the SLN in breast cancer [9]. Concurrent with their investigation, Drs. Reintgen and Cox were developing a combined radiocolloid and blue dye technique for mapping both melanoma and breast cancer patients [10].

Initially, SLNs harvested in melanoma patients using blue dye were examined with routine hematoxylin and eosin staining (H&E). The next critical step to evolve and elevate SLN biopsy to universal application was the ability of the pathologists to focus on the one or two nodes in the basin most at risk for metastasis for detailed pathologic exam. The ability of this concentrated evaluation to allow more accurate staging became evident. This was demonstrated in melanoma in a seminal work by Greshenwald et al. [11]. Ten of 243 patients with histologically negative SLNs were found to have a nodal recurrence in a previously mapped basin. The SLNs from these 10 patients, upon reevaluation with serial sectioning and immunohistochemistry (IHC) stains, demonstrated micrometastatic disease in 80% (8/10) of the cases. These negative SLN biopsies did not represent surgical lymphatic mapping failures, but rather the limitations of routine histologic examination. More refined techniques were developed to detect nodal metastasis in melanoma after Heller et al. observed that some histologically negative lymph nodes placed in tissue culture with conditions primed for growing melanoma cells demonstrated viable melanoma cells in 30% of node-negative cases [12, 13].

As technology evolved, so did the ability to identify tumor cells in lymph nodes that were, until recently, undetectable. H&E is able to identify one tumor cell in a background of 10,000 normal cells, IHC staining identifies one tumor cell in a background of 100,000 normal cells, and reverse transcriptase-polymerase chain reaction (RT-PCR) can assay for one tumor cell in a background of 1 million normal lymphocytes. PCR is a laboratory process in which a particular DNA segment is rapidly replicated in order to produce a larger quantity of DNA for chemical analysis. Initially, melanoma cells were detected using RT-PCR for evaluation of the tyrosinase enzyme, which has a specific marker for metastatic melanoma cells [14].

The aforementioned techniques were developed for the evaluation of malignant melanoma patients. However, the success of this "ultra staging" as the definitive prognostic indicator for melanoma raises a new standard for all solid tumor systems and brings into question the significance of nodal evaluation as the ultimate predictor of metastatic potential.

Lymphatic mapping and SLN biopsy have rapidly evolved in the past decade. Only 10 years ago, the seminal work by Morton et al. was published and has now become the standard of surgical care for melanoma. A similarly rapid acceptance is occurring in breast cancer, and other solid organ tumors may follow. Despite the rapid assent of SLN biopsy into clinical practice, numerous controversies remain. We have attempted to outline in a concise manner the facts and controversies surrounding lymphatic mapping for solid tumors.


   MELANOMA
Top
 Learning Objectives
 Abstract
 Introduction
 Melanoma
Breast
 Colon
 Conclusion
 References
 General References
 
Lymphatic mapping for melanoma has become the springboard for this technology to be applied in oncologic clinical practice and is now accepted as standard therapy. However, some controversial issues question what would seem straightforward, for instance: Who should undergo lymphatic mapping? The Lakeland Regional Cancer Center (LRCC) performs SLN biopsies on all patients with melanomas with a Breslow thickness greater than 0.76 mm; however, many centers use a cutoff of 1.0 mm. Five to six percent of patients with melanoma with a Breslow thickness of 0.76-1.0 mm will be found to have metastatic disease in an SLN when a detailed histologic evaluation is performed [15]. Because this finding has such a significant impact on prognosis and treatment, it is reasonable to perform the procedure for a 5% yield. Ulceration and deeper Clark’s level of the primary can also help guide this decision [16, 17].

Sentinel lymph nodes can now be investigated by more extensive pathologic evaluation. The findings of disease with these more sensitive techniques, however, may have raised more questions than have been answered. Now that micrometastatic disease can be detected with S-100 and even RT-PCR, the question remains as to the clinical significance of detecting one cancer cell in the background of 1 million normal cells. Can this low burden of disease be adequately managed by the patient’s immune system, especially if the SLN bearing an isolated tumor cell is removed? Is the disease confined to the SLN or is the status of the SLN a predictor of risk of distant metastasis?

The Eastern Cooperative Oncology Group (ECOG) trials supporting adjuvant interferon (IFN)-alpha 2B included both T4N0 patients and patients with stage III disease. Adjuvant IFN was shown in these trials to improve overall and disease-free survival. However, only 11%, 25%, and 28% of patients in the ECOG 1684, 1690, and 1694 trials, respectively, were T4N0. This staging was almost exclusively without the benefit of SLN biopsy; 0%, 5%, and 28% of patients underwent SLN biopsy in the respective trials [18-20]. Therefore, the benefit of IFN in T4 node-negative patients based on SLN biopsy was not very well addressed.

With ultra staging, patients classified as node negative based on an SLN biopsy and IHC and RT-PCR analyses are expected to have a much better prognosis than historically staged node-negative patients [21]. Dessureault et al. reviewed a multi-institutional database of 14,914 node-negative patients [22]. Retrospective analysis revealed a statistically significant survival advantage of SLN biopsy in node-negative patients with melanoma less than 1 mm. Five-year survivals were 90.5%, 77.7%, and 69.8%, respectively, for patients staged node negative by SLN biopsy, ELND, and clinical examination alone. This supports the ability of SLN biopsy to upstage patients traditionally deemed node negative and to select a group of patients with a high likelihood of cure by surgery alone. It also supports the general feeling that, even with an ELND, micrometastatic disease is missed. The answer to this question will hopefully be elucidated upon completion of the currently ongoing ECOG trial. ECOG 1697 is randomizing T3-T4N0 patients, or T1-T4N1 microscopic disease (<2 mm micrometastasis in only one node), to receive observation or 4 weeks of high-dose IFN-alpha 2b. SLN biopsy is encouraged in this trial, though it is not required.

The ability of IHC staining to identify malignant cells previously unrecognized has been clearly established. Previously, through more focused evaluation, SLN-negative patients with a regional nodal basin recurrence have been shown to have microscopic disease in the original SLN in the majority of cases. Specifically, 80% of patients who suffered a nodal recurrence of melanoma following a negative SLN biopsy were found to have malignant cells in the SLN upon immunostaining on a retrospective analysis [11]. These negative SLN biopsies did not represent surgical lymphatic mapping failures, but rather the limitations of routine histologic examination.

Shivers et al. demonstrated an increased recurrence rate among SLNs that were pathologically negative but RT-PCR positive compared with patients with SLNs negative both pathologically and by RT-PCR [21]. The recurrence rate was 61% for both pathologically and RT-PCR-positive patients, 13% if pathologically negative but RT-PCR positive, and 2% if negative by all modalities. This study demonstrated submicroscopic disease in the SLNs, predicted melanoma recurrence, and identified clinically significant disease. In addition, if the SLN was negative by this modality, the risk of recurrent disease might be negligible.

If an SLN is positive, the standard recommendation is for systemic IFN and complete lymph node dissection (CLND) of the respective basin. The benefit of CLND to improve overall survival, especially if systemic treatment is initiated, is unknown. At what SLN tumor burden a CLND would impact survival is currently under investigation in the Florida Melanoma II Trial (FMT II). In part I of the trial, patients’ SLNs are evaluated by routine histology, IHC staining, and RT-PCR. In part II, patients with a positive SLN receive IFN and are randomized to observation or CLND. The patients are randomized based on H&E, S-100, or RT-PCR detectable disease in the SLNs. This trial is actively accruing patients and will, hopefully, shed some light on the controversy of who benefits from a CLND in the face of a positive SLN.

An area of controversy surrounds the iliac nodal basin draining the lower extremity or lower trunk. It has long been held that all lymphatic drainage from the lower extremity must first pass through the groin prior to entrance into the iliac basin. Specifically, historical teaching indicates that lymphatic drainage from the superficial groin must first pass through Cloquet’s node to enter the pelvis. This has prompted some to argue that the iliac nodal basin does not need to be approached unless Cloquet’s node is involved with metastatic disease, and therefore, Cloquet’s node essentially functions as an SLN for the iliac basin. Other predictors of iliac nodal involvement and need for complete dissection include four or more superficial groin nodes involved with disease [23, 24].

We have imaged iliac lymph nodes on lymphoscintigraphy from skin injections of the lower extremity, perineum, and lower trunk. It has been our practice to treat these nodes as SLNs and to perform an SLN biopsy regardless of the status of the superficial groin. In our initial review of this data, our bias was supported in that pelvic SLNs could be positive in the face of negative superficial groin SLNs. Of the patients who were noted to have direct afferent lymphatic drainage to the iliac nodal basins, four patients had evidence of micrometastatic disease, with three of those four patients having the iliac nodes identified as the only sites of metastatic disease [25]. This prompted a trial to harvest all pelvic SLNs identified on preoperative lymphoscintigraphy or intraoperative gamma-probe detection. Of the 53 patients studied, 12/53 (22.6%) had positive superficial groin nodes, with positive pelvic SLNs found in three patients (5.7%). In contrast to our earlier experience, no patients were noted to only have positive sentinel nodes in the pelvic area. As a result of this larger series, LRCC clinicians no longer perform biopsies on pelvic nodes identified as SLNs on preoperative lymphoscintigraphy, but limit SLN biopsy to the superficial groin. However, the question of when to perform a biopsy on the pelvic nodes remains controversial.

The issue of when to proceed with a deep inguinal dissection also remains unanswered. Some feel that the presence of deep inguinal disease portends such a poor prognosis and the presence of systemic disease that surgical intervention is meaningless. The counterpoint is that patients with microscopic disease only in the deep inguinal nodes may be cured by CLND. It is accepted that the combination of a superficial and deep dissection is associated with increased morbidity. There exist three approaches to the problem of how aggressive a groin dissection to perform in patients with a positive inguinal SLN: A) perform a combined dissection in all patients; B) perform only a superficial node dissection in all patients, or C) perform a deep dissection selectively. The most reliable predictors of deep inguinal involvement include the presence of four or more positive superficial lymph nodes or a positive Cloquet’s node. However, others have reported positive deep inguinal disease in the face of only microscopic superficial disease [26]. At this point, it is unclear which patients will benefit from a deep inguinal nodal dissection. The American College of Surgeons Oncology Group (ACOSOG) is currently considering a randomized prospective study to answer this question.


   BREAST
Top
 Learning Objectives
 Abstract
 Introduction
 Melanoma
 Breast
Colon
 Conclusion
 References
 General References
 
Lymphatic mapping for breast cancer is rapidly becoming the standard of care. The driving forces behind this rapid acceptance are mainly a result of the accuracy of the procedure with a significant decrease in morbidity over the old standard of care, a level I and II node dissection. Other driving forces include economics, patient choices, and the major trend in shifting to outpatient care. Despite the rapid rise in acceptance of lymphatic mapping and SLN biopsy for staging of breast cancer, many controversial topics remain.

One of the major initial concerns with the technique included the ability to identify the SLN and the false-negative rate. Studies have shown factors related to inability to identify the SLN, most important of which includes the surgeon’s volume [27, 28]. Patient factors shown to increase the likelihood of not finding the SLN include increasing age and body mass index [29]. The accuracy of SLN mapping to predict the status of the axillary basin has been born out in many studies. In 1994 at the Moffitt Cancer Center (MCC), a phase I trial was performed of SLN biopsy followed by complete axillary lymph node dissection (CALND) and reflects much of the similar studies done during the initial learning curve of this technology. In the MCC study, the SLN was successfully identified in 2,036 of 2,100 patients (97.07%). Failure to intraoperatively identify an SLN in the axilla occurred in 64 of 2,100 patients (3.0%). This compares with a rate of successful mapping in 1,534 of 1,717 patients (91.5%) included in a systematic review of 12 studies. The failure rate, therefore, was 142 of 1,676 (8.5%). In patients in our own series in whom mapping failed, a CALND was performed, and metastatic disease was documented in 14 of 64 patients (21.9%). The data for the first 186 patients mapped (phase I), in whom a simultaneous CLND was performed following SLN biopsy, revealed one false-negative SLN biopsy, resulting in a false-negative rate of 0.84%. After this initial experience, patients had SLN removal, and a CLND was performed only if the SLN was positive (615 patients) or could not be identified (64 patients). In the remaining 1,914 patients who have had only a negative SLN biopsy, there have been no axillary recurrences (Fig. 1Go).



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  		Figure 1. Moffitt Cancer Center experience for sentinel lymph node biopsy in breast cancer patients, including initial phase I study.

 
The technique of injecting the radioactive colloid and blue dye has been a matter of great debate. The combination technique appears to be the most accurate in identifying all SLNs. It also appears that there is often more than one SLN. In a prospective multi-institutional study of 1,436 patients, the false-negative rate was 14.3% if a single SLN was removed versus 4.3% if multiple SLNs were removed. This study demonstrates persistence pays off and that all SLNs must be removed in the initial operation [30].

The various injection techniques include intraparenchymal, dermal or subdermal, and subareolar plexus. All three techniques have been shown to be reliable in experienced hands. The dermal technique has been shown by McMasters et al. [31] to identify the SLN in the axilla with increased frequency: 98% SLN identification rate compared with 90% for a peritumoral parenchymal technique. No difference in false negatives was observed, and the dermal technique results in significantly higher counts in the SLN. The dermal technique compares favorably with the peritumoral injection for concordance and false negatives as well as offering many advantages [31]. The subareolar technique has recently been championed by Kern and Klimberg and offers many of the advantages of the dermal injection: it is easy, it avoids the need for image-guided injection, and it increases the distance from the tumor to the SLN, thus eliminating shine through from upper outer quadrant lesions. The transit time is also quicker than the peritumoral technique [32]. In spite of the many advantages of a dermal or subareolar technique, some institutions continue to utilize an intraparenchymal injection, because this is the only technique that will identify internal mammary lymph nodes.

The role of internal mammary dissection has been hotly debated in the circles of breast cancer surgeons for over a century. The idea of dissecting out the internal mammary nodes (IMNs) for breast cancer can be traced back to Harvey Cushing in 1898 [33]. Interest in evaluating IMNs has recently been rejuvenated with the advent and widespread acceptance of lymphatic mapping and SLN biopsy in breast cancer. Unlike the radical resections performed in the past, IMN SLN biopsy is associated with minimal morbidity and can be routinely performed in an outpatient setting; however, proponents believe the findings can have significant implications for both prognosis and treatment. This is reflected in the sixth edition of the 2002 American Joint Commission on Cancer staging manual [34]. Metastases to IMNs are now staged as N1, N2, or N3, based on tumor burden and method of detection. This new staging system more accurately reflects the prognosis of patients with IMN disease. Patients with axillary-negative and IMN-positive nodal disease have been shown to have a similar prognosis to patients with axillary-positive and IMN-negative status, with the combination of metastatic disease in both nodal basins having an especially poor prognosis.

It has been established, contrary to traditional thinking, that IMN drainage is not limited to tumors of the medial quadrant. All regions of the breast can drain to the IMN with similar frequency [35-37]. Proponents of evaluating the IMN basin if lymphatic mapping points to this site as primary drainage argue that this is the whole purpose of the SLN theory. By utilizing this technology, individual patients can have treatment customized to their specific disease status, whether this includes systemic cytotoxic therapy, CALND, or IMN radiation. Despite increased debate, the issue of selective IMN dissection based on lymphatic mapping remains a very controversial issue.

Another area of intense debate revolves around the indication for lymphatic mapping. The issue of mapping for patients with a diagnosis of ductal carcinoma in situ (DCIS) or in patients undergoing prophylactic mastectomy remains controversial. MCC and LRCC investigators perform lymphatic mapping and SLN biopsy for all patients with DCIS. Our reasoning for this has at times been misunderstood. All would agree that patients with DCIS have an excellent long-term prognosis (98% survival). Our major impetus to perform lymphatic mapping on patients with DCIS is that 10%-29% will be found at definitive surgery to have an invasive cancer, which has been confirmed by multiple studies [38-43]. More importantly, there is no way to predict preoperatively which patients with DCIS will be upstaged to invasive cancer at the time of definitive surgery. The rate of upstaging is unrelated to grade of DCIS, whether the biopsy was a core biopsy or excisional biopsy, mean number of core specimens obtained, level of suspicion, lesion size, distribution of calcifications, morphology of calcifications, or patient age [38, 43]. Therefore, no factors exist to distinguish between patients with DCIS and those upstaged to invasive carcinoma at definitive surgery.

Between 28% and 53% of patients with DCIS will undergo mastectomy as definitive treatment [38-41]. Lymphatic mapping is less reliable after a lumpectomy and impossible after a mastectomy. If the SLN biopsy is not performed at the time of the definitive operative procedure, a significant number of patients (>=10%) will be found to have an invasive cancer, which will require a second operative procedure and, in all likelihood, CALND. The majority of these patients will be found to have a negative axilla, yet miss out on all the advantages of SLN biopsy if not performed initially. Clinicians at LRCC and MCC acknowledge that this area remains controversial but still feel the procedure is indicated in this population of patients.

The role of lymphatic mapping at the time of prophylactic mastectomy is also based on similar reasoning. Approximately 5% of patients will be found to have an incidental malignancy [44, 45]. SLN biopsy is simple to perform at the time of mastectomy, with little added morbidity. If a breast cancer is incidentally discovered and the SLN is negative, a CALND can be avoided. SLN biopsy is also a good method to screen the breast for an occult cancer.

The indication for CALND, only a decade ago the standard for all breast cancer patients, is being questioned with increasing frequency. Only 40%-50% of patients with a positive SLN will be found to have further disease in the nonsentinel lymph nodes. Studies have shown that the size of the primary tumor and tumor burden in the SLN are the major determinants for nonsentinel lymph node involvement with metastatic disease [46, 47]. However, the risk of further nonsentinel lymph node disease is significant, even with micrometastasis in the SLNs. There is not yet a tumor burden identified below in which CALND can be routinely omitted. In a study by Turner et al., 26% of patients with only micrometastasis to the SLN had nonsentinel lymph node tumor involvement at the time of CALND [48]. Rahusen et al. reported similar findings with nonsentinel lymph node metastasis in 27% of patients, with only micrometastasis <1 mm identified in the SLN [49]. The finding of micrometastases in the SLN is becoming a more common occurrence with lymphatic mapping and focused pathologic analysis of a few SLNs. In a review from the John Wayne Cancer Institute of 194 breast cancer patients with a positive SLN, 23% had H&E micrometastases (<2.0 mm). In 25% of patients, SLN metastases were detected by cytokeratin (CK)-IHC and had a median size of 0.14 mm, including 15 cases with CK-isolated tumor cells only [48]. In our recent review, even if tumor cells were identified in the SLN by CK-IHC only, and no H&E disease was identified, 14.5% of these patients were found to have H&E disease in the axillary basin at the time of CALND, utilizing standard pathologic techniques. This group would have been incorrectly staged as N0 had CALND not been performed based on the IHC findings [50].

The role of IHC staining of the SLNs also remains an area of significant controversy. SLN biopsy and a focused pathologic evaluation have resulted in upstaging of approximately 10%-20% of breast cancer patients [51-54]. The question is whether this detectable disease is clinically significant. Many advocates for IHC analysis argue that the data show micrometastatic disease to be clinically relevant, and 30% of node-negative breast cancer patients who recur are most likely the same group now being upstaged by CK-IHC. The counter argument is that all the present literature is retrospective in nature and the results are very inconclusive. Therefore, until we have good data, clinical decisions should not be made based on inadequate studies.

We continue to advocate CK-IHC analysis of SLNs, which is much more efficient than evaluation of SLNs by routine histology, and it allows the pathologist to use current technology to be more efficient. A pathologist may be able to detect small volume disease in an SLN by painstaking review of H&E slides or find the same disease rapidly through evaluation of a CK-IHC slide. The same information can be gained, though much more efficiently. A tumor cell is a tumor cell regardless of whether it is stained with a pink or black stain. The question is not if a CK-IHC-identified isolated tumor cell is really a tumor cell but if that low tumor burden is of clinical significance.

Our main purpose for utilizing CK-IHC analysis of SLNs is to avoid false-negative SLN biopsies. Lymphatic mapping and SLN biopsy for breast cancer remains approximately 5 years behind its utilization in melanoma. When investigators first began SLN biopsy in 1994 for breast cancer, we already had much experience with the technology for evaluation of patients with melanoma. In melanoma, false negatives occurred because immunostains were not routine during the initial application of lymphatic mapping for melanoma, resulting in recurrence in the nodal basin because of missed micrometastatic disease [11]. It was in this historical context that CK-IHC was used in evaluation of SLNs in breast cancer. The purpose was to reduce false negatives; the information was not meant to be used as an independent prognosticator. By utilizing CK-IHC of SLNs, and CALND when positive, the absolute false-negative rate was reduced by 2.6% [50].

Clearly, the clinical significance of CK-IHC-only disease is not clear at the current time. The need for CALND in patients with a positive SLN who will receive systemic cytotoxic therapy and radiation to the breast (including the lower axillary nodes) is also controversial. At the time of this printing, CALND for the patient with a positive SLN remains the standard of care. Randomized, multi-institutional prospective studies are ongoing to answer the questions that include: A) the clinical significance of CK-IHC-positive only SLNs, and B) the role of CALND in a patient with a positive SLN. Both of these studies are supported by ACOSOG.


   COLON
Top
 Learning Objectives
 Abstract
 Introduction
 Melanoma
 Breast
 Colon
Conclusion
 References
 General References
 
As a result of the success of SLN biopsy in melanoma and breast tumors, the technique is now being applied to other solid tumors in the gastrointestinal (GI) tract. Reports of SLN biopsy for GI tumors are increasing in frequency and include colorectal cancer (CRC), esophageal, and gastric cancer, as well as the use of laparoscopic procedures. Since the topic in general remains controversial, we will reserve our comments to the most common application: colorectal malignancies through an open surgical approach.

Studies of this procedure are being reported with increased frequency. Opponents of the procedure believe that it is unlike the application of lymphatic mapping to breast cancer and melanoma. In these tumors, most patients are found to be node negative, and avoiding CLND decreases the morbidity of the procedure. In colon cancer, the same operation is usually performed. The resection is unaffected by the decision to perform an SLN biopsy, and therefore, morbidity is unchanged. Without a change in the aggressiveness of resection, one of the major impetuses to perform lymphatic mapping is lost.

The SLN theory for CRC, however, appears to have the same potential for detecting previously unrecognized disease and provides better nodal staging. Up to 30% of node-negative patients with CRC develop a recurrence and die of distant metastasis. It is postulated that this group of patients may have occult lymph node micrometastasis not identified at the time of colon resection and conventional pathologic evaluation. Some series to date appear to support this and have shown that SLN biopsy with focused pathologic evaluation upstages a percentage of patients with colon cancer from stage II to stage III. Stage I and some stage II patients are not typically treated with chemotherapy off study protocol. As in other tumors, it is hypothesized that micrometastasis in CRC detected by lymphatic mapping and focused pathologic techniques may be an efficient method of upstaging patients at high risk for recurrence who should be offered adjuvant therapy.

In 1994, Greenson et al. reviewed 50 cases of Dukes’ B CRC, including 568 pericolic lymph nodes [55]. Fourteen previously node-negative patients stained positive for CK. Six of these patients died and only one patient with a CK-negative lymph node died of colon cancer. The Dukes’ B CK-positive patients behaved clinically similar to Dukes’ C patients, and as importantly, the Dukes’ B CK-negative patients had survival similar to patients with Dukes’ A disease. This study was a retrospective evaluation of patients who had previously undergone colectomy without the aid of lymphatic mapping. Even with these limitations, this study clearly demonstrates the power of a focused lymph node evaluation to upstage patients identified to be at risk for distant spread or who are cured with the surgical procedure.

A prospective study of stage II colorectal patients was reported in 1998 [56]. One hundred ninety-two lymph nodes from 26 patients were evaluated using carcinoembryonic antigen (CEA)-specific nested RT-PCR. Micrometastases were detected in 14 patients (54%). The adjusted 5-year survival rate was 50% in this group compared with 91% in the patients with no micrometastasis detected. Again, no lymphatic mapping was performed. Rosenberg et al. reported a similar finding for RT-PCR specific for CEA and CK-20 [57]. These studies are certainly compelling; however, as in breast and melanoma, not all the literature supports the negative prognostic value of micrometastatic disease [58, 59]. The next step is to identify these patients prospectively and determine if adjuvant chemotherapy would benefit this select group as opposed to all Dukes’ B patients.

Lymph node metastases for CRC remain the strongest prognostic factor, as in other solid tumors. Despite this, up to 30% of patients staged as node negative by routine histology are at risk of dying from their disease. A similar historical sequence as seen in melanoma and breast cancer is now unfolding in CRC. Methods have been developed to help enhance the detection of lymph node metastasis, including serial sectioning, IHC staining, and RT-PCR. All of these techniques remain too expensive and impractical to perform on all lymph nodes. As in the other tumors discussed, the best application of these emerging technologies (lymphatic mapping with SLN biopsy and focused pathologic analysis of lymph nodes, including multistep sectioning, IHC staining, and genetic markers) is when they are applied concomitantly.

Many reports of SLN biopsy in CRC are emerging [60-68]. These studies vary from small single-institution reviews to prospective multi-institutional studies. Not only does the number of patients significantly vary but so do the techniques. Presently, there is no standardization; both single- and combined-agent injection techniques have been utilized, such as subserosal and submucosal injection, in vivo and ex vivo injection methods, and in vivo and ex vivo SLN identification. As expected with a new and evolving technique, the results are also extremely varied. With false-negative rates from 0%-45%, the mean number of SLNs identified varied from a low of one to physicians arbitrarily choosing to count only the first four blue lymph nodes as SLNs. Identification of an SLN occurred in anywhere from 71%-100% of cases. These results would appear to represent a steep learning curve for a new technique.

It would seem logical that the mapping agent should be injected near the tumor with as little mobilization of the colon as needed prior to injection. When the colon is significantly mobilized and at the extreme when lymphatic mapping has been performed ex vivo, vital lymphatics could easily be disrupted and aberrant lymphatics might never be identified. Whether concordance exists between a submucosal and subserosal injection is also unknown at this time. Are two agents better than a single agent? Injecting submucosally or with radiocolloid does require more planning. Colonoscopy must be performed intraoperatively or a day prior and results in colonic distention, patient inconvenience, and increased expense.

Draining to aberrant lymphatics outside the field of a standard oncologic mesenteric resection has been reported in some studies [61, 63, 64]. The frequency thus far appears to vary between 0%-10%. In some cases, this aberrant lymph node has been found to be the only positive lymph node (not unlike the earlier studies of breast cancer and melanoma). Should a more extensive procedure be performed to remove SLNs identified outside the standard field of resection? Most visceral arguments would certainly appear to support that these nodes could upstage a patient. Unfortunately, as reasonable as this argument is, to date there are no data to support it.

The results to date suggest that lymphatic mapping and SLN biopsy in rectal cancer is not as successful as its application in colon tumors. Also, the mesentery of the rectum should not be disturbed until the pathologist can perform assessment of lateral margins. This limits the utility of this technique for primary rectal tumors, and many surgeons are using this as a contraindication for mapping.

The false-negative rate with colon cancer mapping varies widely between studies. Some of this may reflect technique; however, one of the obvious reasons for this difference is the definition of a false negative. If IHC staining and RT-PCR are used, then the false-negative rate is much lower. However, is it reasonable to say that an SLN that is only found to be positive by IHC when a non-SLN is positive by H&E is not a false negative? This is critical because the literature to date is contradictory on the significance of micrometastasis in CRC. These questions are currently being addressed in prospective fashions in breast cancer (ACOSOG Z0010) and melanoma (FMT II). Does the 10%-25% of patients upstaged by lymphatic mapping and focused pathologic analysis of SLNs represent some of the historical 30% of node-negative CRC patients who later develop metastatic disease? Can we presume so based on the limited data at this time and give systemic cytotoxic chemotherapy to these upstaged patients? Should we wait until we have more definitive data, and will a patient presenting today with only micrometastatic disease in a lymph node, previously undetectable, accept observation? It appears, at this time, that the whole concept of SLN biopsy in CRC is controversial, and the data have begged more questions than answered. Hopefully, through sound science, these unanswered questions will be addressed in the near future.


   CONCLUSION
Top
 Learning Objectives
 Abstract
 Introduction
 Melanoma
 Breast
 Colon
 Conclusion
References
 General References
 
Lymphatic mapping and SLN biopsy are able to provide the pathologist with a limited number of lymph nodes to allow a focused analysis. This has resulted in a select group of patients staged as node negative by SLN biopsy, who have more likely been cured by the surgical intervention alone. This surgical evaluation is also performed at a decreased morbidity and avoids CLND in the majority of patients with breast cancer and melanoma. Despite the rapid acceptance of SLN biopsy into clinical practice, many controversies remain, which we have attempted to highlight in this review.


   ACKNOWLEDGMENT
Top
 Learning Objectives
 Abstract
 Introduction
 Melanoma
 Breast
 Colon
 Conclusion
 References
 General References
 
Douglas Reintgen is a member of the Speakers’ Bureau for Schering Oncology.


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 Melanoma
 Breast
 Colon
 Conclusion
 References
General References
 

  1. Sappey M. Injection, preparation et conservation des vaisseaux lymphatiques. These pour le doctorat en medecine, 1843:241.
  2. Uren RF, Howman-Giles R, Thompson JF et al. Lymphoscintigraphy to identify sentinel lymph nodes in patients with melanoma. Melanoma Res 1994;4:395–399.[CrossRef][Medline]
  3. Godellas CV, Berman CG, Lyman G et al. The identification and mapping of melanoma regional nodal metastases: minimally invasive surgery for the diagnosis of nodal metastases. Am Surg 1995;61:97–101.[Medline]
  4. Kamath D, Rapaport D, DeConti R et al. Redefining cutaneous lymphatic flow: the necessity of preoperative lymphoscintigraphy in the management of malignant melanoma. J Fla Med Assoc 1997;84:182–187.
  5. Uren RF, Howman-Giles RB, Shaw HM et al. Lymphoscintigraphy in high-risk melanoma of the trunk: predicting draining node groups, defining lymphatic channels and locating the sentinel node. J Nucl Med 1993;34:1435–1440.[Abstract/Free Full Text]
  6. Cabanas RM. An approach for the treatment of penile carcinoma. Cancer 1977;39:456–466.[CrossRef][Medline]
  7. Morton DL, Wen DR, Wong JH et al. Technical details of intraoperative lymphatic mapping for early-stage melanoma. Arch Surg 1992;127:392–399.[Abstract]
  8. Giuliano AE, Kirgan DM, Guenther JM et al. Lymphatic mapping and sentinel lymphadenectomy for breast cancer. Ann Surg 1994;220:391–401.[Medline]
  9. Krag DN, Weaver DL, Alex JC et al. Surgical resection and radiolocalization of the sentinel lymph node in breast cancer using a gamma probe. Surg Oncol 1993;2:335–339.[CrossRef][Medline]
  10. Albertini JJ, Lyman GH, Cox C et al. Lymphatic mapping and sentinel node biopsy in the patient with breast cancer. JAMA 1996;276:1818–1822.[Abstract]
  11. 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;16:2253–2260.[Abstract]
  12. Heller R, Becker J, Wasselle J et al. Detection of submicroscopic lymph node metastases in patients with melanoma. Arch Surg 1991;126:1455–1460.[Abstract]
  13. Heller R, King B, Baekey P et al. Identification of submicroscopic lymph node metastases in patients with malignant melanoma. Semin Surg Oncol 1993;9:285–289.[Medline]
  14. Wang X, Heller R, VanVoorhis N et al. Detection of submicroscopic lymph node metastases with polymerase chain reaction in patients with malignant melanoma. Ann Surg 1994;220:768–774.[Medline]
  15. Haddad FF, Reintgen DS. Sentinel lymph node biopsy for melanoma. In: Eric DR, Whitman D, eds. Surgical Technique. Radioguided Surgery. Austin: Landed Bioscience, 1999:70.
  16. Shaw HM, McCarthy WH, McCarthy SW et al. Thin malignant melanomas and recurrence potential. Arch Surg 1987;122:1147–1150.[Abstract]
  17. Slingluff Jr CL, Vollmer RT, Reintgen DS et al. Lethal "thin" malignant melanoma. Identifying patients at risk. Ann Surg 1988;208:150–161.[Medline]
  18. Kirkwood JM, Strawderman MH, Ernstoff MS et al. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 1996;14:7–17.[Abstract]
  19. Kirkwood JM, Ibrahim JG, Sondak VK et al. High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190. J Clin Oncol 2000;18:2444–2458.[Abstract/Free Full Text]
  20. Kirkwood JM, Ibrahim JG, Sosman JA et al. High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21 vaccine in patients with resected stage IIB-III melanoma: results of intergroup trial E1694/S9512/C509801. J Clin Oncol 2001;19:2370–2380.[Abstract/Free Full Text]
  21. Shivers SC, Wang X, Li W et al. Molecular staging of malignant melanoma: correlation with clinical outcome. JAMA 1998;280:1410–1415.[Abstract/Free Full Text]
  22. Dessureault S, Soong SJ, Ross MI et al. Improved staging of node-negative patients with intermediate to thick melanomas (>1 mm) with the use of lymphatic mapping and sentinel lymph node biopsy. Ann Surg Oncol 2001;8:766–770.[Abstract/Free Full Text]
  23. Finck SJ, Giuliano AE, Mann BD et al. Results of ilioinguinal dissection for stage II melanoma. Ann Surg 1982;196:180–186.[Medline]
  24. Coit DG, Brennan MF. Extent of lymph node dissection in melanoma of the trunk or lower extremity. Arch Surg 1989;124:162–166.[Abstract]
  25. Puleo C, Cruse CW, Lowe J. Re-definition of pelvic cutaneous lymphatic drainage based on lymphatic mapping principles. Melanoma Res 2001;11(suppl 1):S104.
  26. Karakousis CP, Emrich LJ, Driscoll DL et al. Survival after groin dissection for malignant melanoma. Surgery 1991;109:119–126.[Medline]
  27. McMasters KM, Wong SL, Chao C et al. Defining the optimal surgeon experience for breast cancer sentinel lymph node biopsy: a model for implementation of new surgical techniques. Ann Surg 2001;234:292–300.[CrossRef][Medline]
  28. Cox CE, Salud CJ, Cantor A et al. Learning curves for breast cancer sentinel lymph node mapping based on surgical volume analysis. J Am Coll Surg 2001;193:593–600.[CrossRef][Medline]
  29. Cox CE, Dupont E, Whitehead GF et al. Age and body mass index may increase the chance of failure in sentinel lymph node biopsy for women with breast cancer. Breast J 2002;8:88–91.[CrossRef][Medline]
  30. Wong SL, Edwards MJ, Chao C et al. Sentinel lymph node biopsy for breast cancer: impact of the number of sentinel nodes removed on the false-negative rate. J Am Coll Surg 2001;192:684–691.[CrossRef][Medline]
  31. McMasters KM, Wong SL, Martin 2nd RC et al. Dermal injection of radioactive colloid is superior to peritumoral injection for breast cancer sentinel lymph node biopsy: results of a multiinstitutional study. Ann Surg 2001;233:676–687.[CrossRef][Medline]
  32. Kern KA. Lymphoscintigraphic anatomy of sentinel lymphatic channels after subareolar injection of Technetium 99m sulfur colloid. J Am Coll Surg 2001;193:601–608.[CrossRef][Medline]
  33. Halsted WS. A clinical and histological study of certain adenocarcinoma of the breast. Ann Surg 1898;28:557.[Medline]
  34. Greene FA, Page DL, Fleming ID et al. AJCC Cancer Staging Manual. New York: Springer-Verlag, 2002:223-233.
  35. Turner-Warwick RT. The lymphatics of the breast. Br J Surg 1959;46:574–582.[Medline]
  36. Veronesi U, Cascinelli N, Greco M et al. Prognosis of breast cancer patients after mastectomy and dissection of internal mammary nodes. Ann Surg 1985;202:702–707.[Medline]
  37. Ege GN, Clark RM. Internal mammary lymphoscintigraphy in the conservative management of breast carcinoma: an update and recommendations for a new TNM staging. Clin Radiol 1985;36:469–472.[CrossRef][Medline]
  38. Cox CE, Nguyen K, Gray RJ et al. Importance of lymphatic mapping in ductal carcinoma in situ (DCIS): why map DCIS? Am Surg 2001;67:513–521.[Medline]
  39. Burak Jr WE, Owens KE, Tighe MB et al. Vacuum-assisted stereotactic breast biopsy: histologic underestimation of malignant lesions. Arch Surg 2000;135:700–703.[Abstract/Free Full Text]
  40. Lee CH, Carter D, Philpotts LE et al. Ductal carcinoma in situ diagnosed with stereotactic core needle biopsy: can invasion be predicted? Radiology 2000;217:466–470.[Abstract/Free Full Text]
  41. Klauber-DeMore N, Tan LK, Liberman L et al. Sentinel lymph node biopsy: is it indicated in patients with high-risk ductal carcinoma-in-situ and ductal carcinoma-in-situ with microinvasion? Ann Surg Oncol 2000;7:636–642.[Abstract]
  42. Darling ML, Smith DN, Lester SC et al. Atypical ductal hyperplasia and ductal carcinoma in situ as revealed by large-core needle breast biopsy: results of surgical excision. AJR Am J Roentgenol 2000;175:1341–1346.[Abstract/Free Full Text]
  43. Renshaw AA. Predicting invasion in the excision specimen from breast core needle biopsy specimens with only ductal carcinoma in situ. Arch Pathol Lab Med 2002;126:39–41.[Medline]
  44. Lopez MJ, Porter KA. The current role of prophylactic mastectomy. Surg Clin North Am 1996;76:231–242.[CrossRef][Medline]
  45. Dupont EL, Kuhn MA, McCann C et al. The role of sentinel lymph node biopsy in women undergoing prophylactic mastectomy. Am J Surg 2000;180:274–277.[CrossRef][Medline]
  46. Kamath VJ, Giuliano R, Dauway EL et al. Characteristics of the sentinel lymph node in breast cancer predict further involvement of higher-echelon nodes in the axilla: a study to evaluate the need for complete axillary lymph node dissection. Arch Surg 2001;136:688–692.[Abstract/Free Full Text]
  47. Chu KU, Turner RR, Hansen NM et al. Do all patients with sentinel node metastasis from breast carcinoma need complete axillary node dissection? Ann Surg 1999;229:536–541.[CrossRef][Medline]
  48. Turner RR, Chu KU, Qi K et al. Pathologic features associated with nonsentinel lymph node metastases in patients with metastatic breast carcinoma in a sentinel lymph node. Cancer 2000;89:574–581.[CrossRef][Medline]
  49. Rahusen FD, Torrenga H, van Diest PJ et al. Predictive factors for metastatic involvement of nonsentinel nodes in patients with breast cancer. Arch Surg 2001;136:1059–1063.[Abstract/Free Full Text]
  50. Jakub J, Diaz N, Ebert M et al. Completion axillary lymph node dissection minimizes the likelihood of false negatives in patients with invasive breast carcinoma and cytokeratin positive only sentinel lymph nodes. Am J Surg 2002;184:302.[CrossRef][Medline]
  51. Pendas S, Dauway E, Cox CE et al. Sentinel node biopsy and cytokeratin staining for the accurate staging of 478 breast cancer patients. Am Surg 1999;65:500–506.[Medline]
  52. Turner RR, Ollila DW, Krasne DL et al. Histopathologic validation of the sentinel lymph node hypothesis for breast carcinoma. Ann Surg 1997;226:271–278.[CrossRef][Medline]
  53. Sabel MS, Zhang P, Barnwell JM et al. Accuracy of sentinel node biopsy in predicting nodal status in patients with breast carcinoma. J Surg Oncol 2001;77:243–246.[CrossRef][Medline]
  54. Turner RR, Giuliano AE, Hoon DS et al. Pathologic examination of sentinel lymph node for breast carcinoma. World J Surg 2001;25:798–805.[CrossRef][Medline]
  55. Greenson JK, Isenhart CE, Rice R et al. Identification of occult micrometastases in pericolic lymph nodes of Duke’s B colorectal cancer patients using monoclonal antibodies against cytokeratin and CC49. Correlation with long-term survival. Cancer 1994;73:563–569.[CrossRef][Medline]
  56. Liefers GJ, Cleton-Jansen AM, van de Velde CJ et al. Micrometastases and survival in stage II colorectal cancer. N Engl J Med 1998;339:223–228.[Abstract/Free Full Text]
  57. Rosenberg R, Hoos A, Mueller J et al. Impact of cytokeratin-20 and carcinoembryonic antigen mRNA detection by RT-PCR in regional lymph nodes of patients with colorectal cancer. Br J Cancer 2000;83:1323–1329.[CrossRef][Medline]
  58. Jeffers MD, O’Dowd GM, Mulcahy H et al. The prognostic significance of immunohistochemically detected lymph node micrometastases in colorectal carcinoma. J Pathol 1994;172:183–187.[CrossRef][Medline]
  59. Cutait R, Alves VA, Lopes LC et al. Restaging of colorectal cancer based on the identification of lymph node micrometastases through immunoperoxidase staining of CEA and cytokeratins. Dis Colon Rectum 1991;34:917–920.[CrossRef][Medline]
  60. Merrie AE, van Rij AM, Phillips LV et al. Diagnostic use of the sentinel node in colon cancer. Dis Colon Rectum 2001;44:410–417.[CrossRef][Medline]
  61. Bilchik AJ, Nora D, Tollenaar RA et al. Ultrastaging of early colon cancer using lymphatic mapping and molecular analysis. Eur J Cancer 2002;38:977–985.
  62. Tsioulias GJ, Wood TF, Spirt M et al. A novel lymphatic mapping technique to improve localization and staging of early colon cancer during laparoscopic colectomy. Am Surg 2002;68:561–565.[Medline]
  63. Paramo JC, Summerall J, Poppiti R et al. Validation of sentinel node mapping in patients with colon cancer. Ann Surg Oncol 2002;9:550–554.[Abstract/Free Full Text]
  64. Feig BW, Curley S, Lucci A et al. A caution regarding lymphatic mapping in patients with colon cancer. Am J Surg 2001;182:707–712.[CrossRef][Medline]
  65. Bendavid Y, Latulippe JF, Younan RJ et al. Phase I study on sentinel lymph node mapping in colon cancer: a preliminary report. J Surg Oncol 2002;79:81–85.[CrossRef][Medline]
  66. Waters GS, Geisinger KR, Garske DD et al. Sentinel lymph node mapping for carcinoma of the colon: a pilot study. Am Surg 2000;66:943–946.[Medline]
  67. Saha S, Wiese D, Badin J et al. Technical details of sentinel lymph node mapping in colorectal cancer and its impact on staging. Ann Surg Oncol 2000;7:120–124.[Abstract]
  68. Joosten JJ, Strobbe LJ, Wauters CA et al. Intraoperative lymphatic mapping and the sentinel node concept in colorectal carcinoma. Br J Surg 1999;86:482–486.[CrossRef][Medline]

   GENERAL REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 Melanoma
 Breast
 Colon
 Conclusion
 References
 General References
 
Received September 17, 2002; accepted for publication October 24, 2002.




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