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Surgical Management of the Groin Lymph Nodes in Melanoma in the Era of Sentinel Lymph Node Dissection
Richard Essner, MD;
Randall Scheri, MD;
Maihgan Kavanagh, MD;
Hitoe Torisu-Itakura, MD, PhD;
Leslie A. Wanek, DrPH, MD;
Donald L. Morton, MD
Arch Surg. 2006;141:877-884.
ABSTRACT
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Hypothesis Intraoperative lymphatic mapping and sentinel lymphadenectomy (LM/SL) has become an increasingly popular surgical technique for staging the regional lymph nodes in early-stage melanoma. The technique of LM/SL has potentially great advantage for the groin, where the morbidity of superficial groin dissection or iliac dissection can be high. The surgical management of these basins is unknown for patients with tumor-positive sentinel lymph nodes (SNs).
Design Cohort of successive patients undergoing LM/SL over 18 years. Those patients found to have tumor-positive SNs underwent sentinel complete lymph node dissection. Postoperatively, patients were followed up on a routine basis with serial examinations and chest radiography. The median follow-up was 50 months.
Setting Tertiary cancer center.
Patients The technique of LM/SL was performed for 431 consecutive patients. Sentinal lymph nodes were identified in each case. Patients with tumor-positive SNs underwent sentinel complete lymph node dissection.
Intervention Cutaneous lymphoscintigraphy and blue dye with or without use of the gamma probe–directed LM/SL. Sentinel lymph nodes were examined by hematoxylin-eosin staining and immunohistochemistry staining with HMB-45 and S100 protein. Only patients with tumor-positive SNs had sentinel complete lymph node dissection.
Main Outcome Measure Computer-assisted database with statistical analyses using log-rank tests and Cox regression models.
Results Of the 431 patients, 264 (61%) were women and the median age was 50 years (age range, 15-89 years). A majority (86%) of the primary tumors were on the lower extremities, 54% were of Clark level IV or V, and there was a mean ± SD thickness of 1.89 ± 1.59 mm (range, 0.30-14.00 mm). Ninety-three patients (21%) were found to have tumor-positive SNs. After LM/SL and sentinel complete lymph node dissection, 62 patients (67%) were found to have a single tumor-positive lymph node, 25 (27%) had 2 tumor-positive lymph nodes, and 6 (6%) had 3 or more tumor-positive lymph nodes. Only 12 patients (4%) with tumor-negative SNs have had recurrence in the dissected basin. The 5-year overall survival was significantly better for patients with tumor-negative lymph nodes (mean ± SD 5-year overall survival, 94% ± 5%) than for patients with tumor-positive lymph nodes (mean ± SD 5-year overall survival, 75% ± 4%) (P<.01). The tumor status of the Cloquet lymph node was predictive of the tumor status of the iliac lymph nodes. Multivariate analyses with a Cox regression model identified tumor-positive SN (P = .001), primary tumor thickness (P = .03), and ulceration (P = .001) as being predictive of survival. Sex, age, Clark level, and primary site were not significant (P>.05).
Conclusions Our results demonstrate the prognostic significance of LM/SL for early-stage melanoma draining to the groin basin. The accuracy of LM/SL measured by the rare recurrences suggests that this surgical procedure should become standard for patients with early-stage melanoma of the lower extremities and trunk. Sampling of the Cloquet node should be used to determine the need for iliac dissection when a tumor-positive SN is identified in the groin.
INTRODUCTION
The management of the regional lymph nodes in patients with early-stage melanoma remains controversial. As yet, there is no definitive consensus regarding the optimum timing or extent of regional lymphadenectomy. Multiple retrospective single-institutional and prospective randomized clinical trials have failed to demonstrate a survival benefit for patients with early-stage melanoma with nonpalpable lymph nodes who undergo elective lymph node dissection (LND). Many investigators support the notion that regional lymph node metastases are an early sign of distant disease and that only patients with pathologically proven metastases should undergo (therapeutic) LND even though many of the patients are probably not cured by the surgery alone.
Melanomas draining to the inguinal lymph nodes pose an additional problem since groin elective LND or therapeutic lymphadenectomy may be complicated by significant early and/or long-term morbidity, and the addition of deep groin dissection including iliac, hypogastric, and obturator lymph nodes (ilioinguinal LND [ILND]) may further increase the risk of additional complications.1-3 Some investigators1, 4-6 report no survival advantage for the addition of ILND to inguinal dissection, stating that disease-specific factors negate any potential survival benefit, and reserve ILND for palliation only. Other investigators7-11 have demonstrated a survival benefit for subgroups of patients undergoing ILND and believe that ILND is a superior procedure to superficial groin dissection (SGD).
As a result of the controversy in the care of patients with early-stage melanoma, Morton et al12 in 1992 described a minimally invasive alternative to elective LND or delayed therapeutic dissection: intraoperative lymphatic mapping (LM), sentinel lymphadenectomy (SL), and sentinel complete LND (SCLND). This procedure is based on the concept that regional lymph node metastases occur by passage of melanoma cells through afferent lymphatics to the regional basin and to particular identifiable sentinel lymph nodes (SNs). Experiments with cutaneous lymphoscintigraphy and subsequent work with several vital dyes in an animal model demonstrated that SN technology was valid.13-14 A large body of literature supporting the concepts of the original work by Morton and colleagues has accumulated over the past 13 years.15
Although a defined role of LM/SL/SCLND in patient care is unknown, LM/SL has become an increasingly popular alternative to elective LND.16 The attraction of LM/SL/SCLND to both surgeons and patients is that the technique is minimally invasive with little morbidity and is highly accurate for determining lymph node status for staging and directing adjuvant therapy. Patients who have a tumor-positive SN undergo SCLND whereas those with tumor-negative LM/SL are spared the costs and potential morbidity of complete LND.17 The technique of LM/SL/SCLND is particularly attractive for managing patients with primary tumors on the lower extremities and trunk that show lymphatic drainage to the groin lymph nodes. However, there are few data available to demonstrate the accuracy of this technique for the groin basin.
METHODS
Four hundred thirty-one patients with clinical stage I (American Joint Committee on Cancer stage I or II) melanoma who underwent LM/SL and SCLND for tumor-positive SNs between January 1985 and July 2003 were identified from our computer-assisted database. Data were analyzed by patient sex and age as well as by primary tumor site, Breslow thickness, ulceration, and histology of the primary melanoma.18
Preoperatively, patients were routinely evaluated by complete history and physical examinations, chest radiography, and blood profiles, including lactate dehydrogenase levels. In some cases, computed tomography scans of the chest, abdomen, and pelvis, magnetic resonance imaging, or positron emission tomography were used when there was clinical suspicion of distant metastases.19-20 If metastases were identified, patients were excluded from LM/SL. Lymphatic mapping and SL were performed according to the techniques we previously described.12, 21-22 In brief, patients underwent cutaneous lymphoscintigraphy either several days prior to or on the day of the operative procedure.23 The skin site identified by lymphoscintigraphy was marked by the nuclear medicine physician. At the time of surgery, 1.0 to 2.0 mL of isosulfan blue (Lymphazurin 1%; Tyco International, Exeter, NH) was injected intradermally at the primary site. The skin was gently massaged to enhance the drainage of isosulfan blue into the regional lymphatics. An incision was made over the skin site marked by the nuclear medicine physician. The afferent lymphatics were examined for blue staining followed from the edge of the wound to the first SN.
Since 1993, we have routinely used radiolymphoscintigraphy as an adjunct to the blue dye to improve the accuracy of LM/SL. Blue-stained or radioactive SNs were excised and examined for the presence of metastases either by review of frozen sections (early in our experience) or, more commonly, by permanent sections with hematoxylin-eosin staining. If metastases were not demonstrated by hematoxylin-eosin staining of the first sections, additional sections were cut from the bivalved lymph nodes and stained with murine monoclonal antibodies HMB-45 and S100.24 If metastases were identified in the SN, SCLND was recommended and usually performed. Lymph nodes removed by SCLND (either SGD alone or with ILND) were examined only by conventional hematoxylin-eosin staining.
Patient records were reviewed to confirm all of the clinical data, including the location (ie, inguinal or iliac) of the nodal metastases, number of lymph nodes with metastasis, pathologic status of the Cloquet node, and operative procedure performed. The Cloquet node has been defined as the lymphatic tissue medial to the femoral vein at the superior aspect of the femoral canal and is thought to represent the leading lymph node into the pelvis from the inguinal basin.10 The Cloquet lymph node was evaluated by hematoxylin-eosin staining only.
Postoperatively, patients were followed up by routine clinical examination, blood work, and chest radiography. Follow-up time was calculated from initial diagnosis until last follow-up or death. Follow-up ranged from 4 to 198 months (median, 50 months). All of the LM/SL and SCLND procedures occurred within 3 months of diagnosis of the primary melanoma. Survival curves were constructed using Kaplan-Meier estimates.25-26 Differences in survival distributions were tested by the log-rank method. Differences in frequency distributions and proportions were made using either  2 analysis or Fisher exact test. P<.05 was considered statistically significant.
RESULTS
Most patients (61%) were women, a majority (53%) of the patients were aged 50 years or younger (range, 15-89 years), and 86% of the patients had primary tumors on the lower extremities. Primary tumors ranged in thickness from 0.30 to 14.00 mm (mean, 1.89 mm). Fifty-four percent of the primary tumors were of Clark level IV or V, and 15% were ulcerated. Forty-four percent of the primary tumors were superficially spreading histologic abnormalities. Patients with tumor-positive SNs tended to have primary tumors that were of a higher Clark level and were thicker than those in patients with tumor-negative SNs (Table 1).
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Table 1. Comparison of 431 Patients With Tumor-Negative and Tumor-Positive Sentinel Lymph Nodes
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Four hundred thirty-one patients underwent LM/SL, with identification of SN in all of the cases. Three hundred thirty-eight patients (78%) had tumor-negative SNs; 12 (4%) of these patients have subsequently had recurrence in the nodal basin (Table 2). Ninety-three patients (21%) had tumor-positive SNs. Sentinel complete LND was performed in all but 4 cases with tumor-positive SNs. Sixty-two patients (67%) had 1 tumor-positive lymph node, 25 (27%) had 2 tumor-positive lymph nodes, and 6 (6%) had 3 or more tumor-positive lymph nodes identified. Thirty-seven (40%) of the 93 patients with tumor-positive dissections have had recurrence. Forty-nine (11%) of the 431 patients have died. Patients with tumor-positive inguinal SNs underwent SCLND by removal of the entire superficial (inguinal) basin alone (SGD) (n = 20), with sampling of the Cloquet lymph node to determine the need for ilioinguinal dissection (n = 31), or ilioinguinal dissection (ILND) as routine management (n = 38). Four patients with tumor-positive SNs did not undergo SCLND as a result of either patient or physician choice. Sixteen (17%) of the 93 patients with tumor-positive SNs had primary tumors on the trunk. One patient with bilateral tumor-positive inguinal lymph nodes refused SCLND. One patient had an SGD alone. Ten patients had an SGD with sampling of the Cloquet lymph node. In 4 cases, both inguinal and iliac lymph node dissections were performed without knowing the tumor status of the Cloquet node.
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Table 2. Distribution of First-Site Recurrences for 431 Patients With Primary Melanoma of the Lower Extremities and Trunk*
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Seventy-six patients had tumor-positive SNs arising from primary melanoma on the lower extremities. Three patients with tumor-positive SNs refused SCLND. In 19 cases, SGDs were performed. In 21 cases, patients had an SGD performed with sampling of the Cloquet node to determine the need for deep groin dissection. In 33 cases, SGD and deep groin dissection were performed as a single procedure.
The mean ± SD 5-year disease-free survival was significantly worse for patients with tumor-positive dissections (52% ± 9%) than for those with tumor-negative dissections (82% ± 7%) (P<.001) (Figure 1). The difference in disease-free survival translated to a lower mean ± SD overall 5-year survival (75% ± 4% vs 94% ± 5%, respectively; P<.001) (Figure 2). Only Clark level and thickness correlated with greater risk for patients having tumor-positive lymph nodes.
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Figure 1. Overall 5-year disease-free survival estimates for patients with tumor-negative (mean ± SD overall 5-year disease-free survival, 82% ± 7%) and tumor-positive (mean ± SD overall 5-year disease-free survival, 52% ± 9%) sentinel lymph node dissections (SLNDs). Patients with tumor-negative sentinel lymph nodes had significantly better disease-free survival than those with tumor-positive sentinel lymph nodes (P<.001).
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Figure 2. Overall 5-year survival estimates for patients with tumor-negative (mean ± SD overall 5-year survival, 94% ± 5%) and tumor-positive (mean ± SD overall 5-year survival, 75% ± 4%) sentinel lymph node dissections (SLNDs). Patients with tumor-negative sentinel lymph nodes had significantly better survival than those with tumor-positive sentinel lymph nodes (P<.001).
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Fifty-five (16%) of 338 patients with tumor-negative SNs have had recurrence. Nearly half of all (22/25) first-site recurrences were to in-transit sites. Twelve patients (4%) had recurrences to the dissected basin, and 43 (13%) had recurrences to distant sites. The median time to recurrence in the lymph node was 28 months; however, 1 patient had recurrence 132 months after tumor-negative LM/SL.
Thirty-seven (40%) of 93 patients with tumor-positive SNs have had recurrence. Most (31 [84%] of 37) of these recurrences have been to distant sites; they have less commonly been to regional lymph nodes, in-transit sites, or at the wide excision. The median time to distant recurrence for tumor-positive dissections was 7.6 months.
Multiple clinicopathologic features were examined for their role in predicting overall survival. Only tumor thickness, tumor status of the SN, and ulceration were significant (P<.05) (Table 3).
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Table 3. Univariate and Multivariate Analyses of Factors Predicting Overall Survival of 431 Patients Undergoing Lymphatic Mapping and Sentinel Lymphadenectomy for Primary Tumors on the Lower Trunk and Extremities
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A variety of operative procedures were used to manage the regional lymph nodes after LM/SL (Figure 3 and Table 4). The decision for the operative procedure was based on surgeon and perhaps patient choice. The positive predictive value for the tumor status of the Cloquet node to determine the status of the deep groin lymph nodes was 66% (4/7 cases) whereas the negative predictive value was 97% (46/47 cases).
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Figure 3. Summation of tumor-positive dissections and lymph areas dissected. A variety of surgical approaches were used by surgeons based on individual decision.
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Table 4. Additional Tumor-Positive Lymph Nodes Identified by the 4 Operative Procedures and Recurrence Patterns*
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COMMENT
The development of LM/SL has revolutionized the management of patients with early-stage melanoma. The technique allows surgeons to identify the pattern of lymphatic drainage from the primary site to the regional lymph node basin; it provides a basis for removal of the SN and a focused pathologic assessment of the specimen. The staging of the regional lymph nodes in this fashion has led to more homogeneous staging than traditionally expected in these patients. Numerous retrospective studies12-13,15, 18 prior to the development of LM/SL have shown that the 5-year survival of patients with lymph node metastases (American Joint Committee on Cancer stage III) can range between 15% and 70%. This wide range in outcome reflects the historical heterogeneity of patients presenting with American Joint Committee on Cancer stage III disease. The prognostic factors for stage III disease have been defined as patient related, primary tumor related, and lymph node related.9, 18 With the exception of thick primary tumors (>4 mm) of the trunk,27 it is generally accepted that lymph node–related variables are the most important determinant of survival following development of nodal disease. The most important prognostic variables include number of tumor-containing lymph nodes,5, 9 percentage of tumor-positive lymph nodes,28 presence of extracapsular extension,29 macroscopic vs microscopic evidence of disease,29 clinically tumor-positive lymph nodes,5, 30 ulceration of the primary tumor, and highest level of tumor-involved nodes.9 The survival of patients with tumor-negative lymph nodes has been reported to be in the range of 70% to 90%.17-18,30
The development of LM/SL has clearly advanced the methods by which the regional lymph nodes are staged. A majority of patients with tumor-positive SNs will have only a single lymph node with metastases, thereby making the prognosis of most patients with lymph node metastases very uniform; however, these data call for question as to the role of SCLND. Pathologically proven superficial groin nodes are associated with a 30% to 75% 5-year survival.4, 6, 31 Our 75% 5-year survival compares favorably with previous findings.27-30 Regardless of other prognostic factors, the decision for performing a deep groin dissection hinges on the clinical and pathologic status of the superficial inguinal nodes. Clinically tumor-positive inguinal nodes are predictive of pathologically tumor-positive iliac nodes in 15% to 100% of cases.2, 4, 21 Sterne et al31 have found that the degree of clinical nodal involvement is important in predicting iliac node tumor positivity. In their series of 25 patients who underwent ILND, 1 mobile superficial groin lymph node was associated with pathologically tumor-positive iliac nodes in 8 (36%) of cases whereas multiple mobile nodes or fixed nodes were always associated with positive iliac nodes. The incidence of iliac node tumor positivity is also directly related to the number of pathologically tumor-positive inguinal nodes. Finck et al7 have shown that the incidence of tumor-positive iliac nodes increases from 14% when 1 inguinal node is pathologically tumor positive to 50% when 4 or more nodes are involved. Other investigators32 have shown a 100% incidence of iliac node tumor positivity when 3 or more inguinal nodes contain metastatic disease. However, the number of tumor-containing nodes is not easily determined at surgery and is not useful for making decisions on performing ILND after identifying a tumor-positive SN.
Coit et al9 previously reported the status of the Cloquet node to be 79% predictive of occult iliac node metastasis. Our results suggest both the positive and negative predictive values of using the Cloquet lymph node for evaluating the deep groin basin. Although most surgeons would agree that SGD is the mainstay for treatment of groin node metastases, the role of ilioinguinal dissection remains controversial. Some investigators23 have reported that the addition of a deep node dissection is not warranted when the inguinal nodes contain occult metastatic disease since the likelihood of deep node metastases is small. Others5-6 have found this to not be the case. Deep node dissections are most often performed in the presence of clinically evident iliac metastases. Opponents of deep node dissection believe that the high potential morbidity outweighs any survival benefit and that deep node positivity is just a marker of disseminated disease. Previously published 5-year survival rates in patients with pathologically proven deep node metastasis ranged from 0%1 to 34%.2-3 In the modern era of LM/SL, even patients with 2 to 4 tumor-positive lymph nodes have survival estimates of 40% to 50%.18
A review of 294 patients with American Joint Committee on Cancer stage III melanoma to the groin was performed to determine the utility of our management algorithm for deep groin nodes. Superficial groin dissections provided a survival benefit in those patients selected for low-risk factors. However, a 29% 5-year survival following deep groin dissections in patients with histologically tumor-positive deep nodes would seem to indicate that some patients treated by SGD and deep groin lymph node dissection derive a therapeutic benefit from the procedure and that systemic disease is not a universal finding in patients with deep node metastases. Multivariate analysis identified female sex, younger age, and low tumor burden as good prognostic factors associated with survival. The pathologic status of the Cloquet node was superior to the clinical status of the superficial groin nodes for predicting occult iliac node metastases.
Our results demonstrate the importance of LM/SL for staging the regional lymph nodes in early-stage melanoma. These data are consistent with a number of other studies verifying the accuracy of this minimally invasive operative technique. The technique of LM/SL reduces the morbidity and costs of lymph node staging compared with SGDs (with or without deep groin dissections). Although only 3% of the patients had recurrence in the lymph node basin after tumor-negative LM/SL, these recurrences may cause significant morbidity because of the high incidence of synchronous in-transit disease (Table 2).33 Similarly, recurrences following a tumor-positive superficial groin may occur with in-transit disease and potentially increase the risk of patients developing chronic lower extremity pain or lymphedema as a result of treatment. Although the therapeutic value of SCLND is unknown and is being tested (in the Multicenter Selective Lymphadenectomy Trial II), our data suggest that tumor status of the Cloquet node may be the most useful approach to evaluating the tumor status of the deep groin lymph nodes following LM/SL.34
AUTHOR INFORMATION
Correspondence: Richard Essner, MD, John Wayne Cancer Institute, 2200 Santa Monica Blvd, Suite 123, Santa Monica, CA 90404.
Accepted for Publication: May 19, 2006.
Funding/Support: This work was supported by grants CA 12582 and CA 29605 from the National Institutes of Health, Bethesda, Md, and by funding from the Saban Family Foundation, Los Angeles, Calif.
Previous Presentation: This paper was presented at the 77th Annual Meeting of the Pacific Coast Surgical Association; February 20, 2006; San Francisco, Calif; and is published after peer review and revision. The discussions that follow this article are based on the originally submitted manuscript and not the revised manuscript.
Author Affiliations: Roy E. Coats Research Laboratories, John Wayne Cancer Institute, Saint John's Health Center, Santa Monica, Calif.
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Discussion
Stanley Leong, MD, San Francisco, Calif: The authors listed have contributed significantly in the development of lymphatic mapping and sentinel lymphadenectomy in the staging of melanoma. To date, about 80% of the melanoma patients with a negative sentinel lymph node can be spared a more morbid procedure of a regional lymph node dissection. Numerous studies by others have confirmed the utility of this important staging procedure. Thus, lymphatic mapping and sentinel lymphadenectomy for melanoma has been adopted as the standard of care in the staging of melanoma (Leong SP. Curr Treat Options Oncol. 2004;5:185-194).
In this study, Dr Essner and colleagues have summarized a large melanoma database regarding the lymphatic mapping and the sentinel lymphadenectomy in the groin nodal basin, a difficult area to work with and very aptly brought up by the authors that if you do a radical dissection, the morbidity is significant.
They have confirmed their previous publications that 5-year overall survival of patients with primary trunk and extremity melanoma was significantly better for patients with tumor-negative than tumor-positive sentinel lymph nodes. The most important finding perhaps in this study is that only 3.5% (12 of 338) of the patients who had negative sentinel lymph nodes developed nodal basin recurrence. Thus, the false-negative rate is 3.5%, attesting to the fact that the procedure is highly accurate. Further, in the group of 90 patients with positive sentinel lymph nodes, most patients developed distant metastasis (84%) and, less commonly, to regional lymph nodes, in-transit sites, or at the local excision sites. On the other hand, the recurrence rate for the negative sentinel lymph node group is significantly lower. These data suggest that melanoma progression in general is orderly rather than the fact that at inception, it is systemically widespread. The spectrum theory by Hellman says that cancer development is progressive. Before it startsto metastasize, we are able to excise the cancer and potentially cure the patient—a provocative thought. Both the breast cancer and melanoma data in the sentinel lymph node era suggest that the spectrum theory is the most compatible one rather than the Fisher concept that cancer is systemic at the onset or the Halstedian concept that only lymph nodes are involved before systemic spread. The spectrum theory indicates that at an early point of proliferation, it is probably lymphatic bound, and then later, the cancer may become systemically bound (Leong SP. Ann Surg Oncol. 2004;11:192S-197S).
The authors should be congratulated for developing and maintaining a large melanoma sentinel lymph node database to provide evidence-based information to allow us to understand better the biology and clinical outcome of melanoma. Further, it helps us to develop new hypotheses to be tested in clinical trials.
Despite the large database being presented, the subgroups, as you can see in that very busy slide, are st |
