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© 2003 American Society for Clinical Oncology Clinical Outcome of Stage I/II Melanoma Patients After Selective Sentinel Lymph Node Dissection: Long-Term Follow-Up Results
From the Department of Surgical Oncology, VU University Medical Center, Amsterdam, the Netherlands. Address reprint requests to S. Meijer, MD, PhD, VU University Medical Center, Department of Surgical Oncology, PO Box 7057, 1007 MB Amsterdam, the Netherlands; email: s.meijer{at}vumc.nl.
Purpose: Although sentinel lymph node (SLN) status is part of the new American Joint Committee on Cancer staging system, there is no final proof that the SLN procedure in melanoma patients influences outcome of disease. This study investigated the accuracy of the SLN procedure and clinical outcome in melanoma patients after at least 60 months of follow-up. Patients and Methods: Between 1993 and 1996, 209 patients with stage I/II cutaneous melanoma underwent selective SLN dissection by the triple technique. If the SLN contained metastatic disease, a completion lymphadenectomy was performed. Survival analyses were performed using the Kaplan-Meier approach. Factors associated with survival were analyzed using the Cox proportional hazards regression model.
Results: The success rate was 99.5%. Median follow-up was 72 months. Forty patients (19%) had a positive SLN. The false-negative rate was 9%. Five-year overall survival was 87% for the entire group and 92% and 67% for SLN-negative and SLN-positive patients (P < .0001), respectively. All patients with a positive SLN and a Breslow thickness Conclusion: With a success rate of 99.5% and a false-negative rate of 9% after long-term follow-up, the triple-technique SLN procedure is a reliable and accurate method. Survival data seem promising, although a therapeutic effect is still questionable. As shown in this study, not all SLN-positive patients have a poor prognosis.
THE OPTIMAL TREATMENT of patients with cutaneous melanoma regarding the regional lymph node basin has been controversial for many years. Various studies compared elective lymph node dissection (ELND) with the wait-and-watch approach and failed to offer a definitive optimal approach.1–6 However, investigators of the Intergroup Melanoma Trial demonstrated a survival benefit for ELND in prospectively stratified subsets of patients.7 The World Health Organization trial no. 14 showed that survival was significantly better for patients with resected microscopic nodal disease by ELND compared with patients who did not undergo ELND and subsequently developed gross nodal disease.2 It seems that lymph node dissection is thus curative in some patients with nodal metastases. The disadvantage of ELND is that the procedure is applied to all patients who have clinically negative lymph nodes. Therefore, the majority of patients without nodal metastases (approximately 80%) are subjected to the morbidity of ELND without any therapeutic benefit.8 This morbidity is significant and includes wound infection, seroma formation, and lymphedema. The ideal situation would be to only identify those patients with lymph node metastases for therapeutic lymph node dissection. This is possible by removing only the lymph node from the draining lymph basin that is most likely to contain metastases, the sentinel lymph node (SLN). Lymphatic mapping and selective SLN dissection is a minimally invasive procedure associated with limited morbidity. Since the introduction of the SLN procedure in the early 1990s, this procedure is widely used in the management of patients with cutaneous melanoma without clinical evidence of nodal metastases. The SLN concept is based on the theory of an orderly progression of tumor cells in the initial phase of the metastatic progress within the lymphatic system. It assumes that early lymphatic metastases, if present, are always found first within the first tumor-draining lymph node, the SLN. A tumor-negative SLN would thus predict the absence of metastatic disease in the rest of the tumor-draining lymph node basin and negate the necessity of an ELND. Several studies have validated this assumption.8–10 However, there is no final proof that SLN dissection, with selective complete lymph node dissection (LND) for a tumor-involved SLN, improves survival of melanoma patients. So far, the SLN procedure is mainly used for staging of melanoma patients and to select patients for (experimental) adjuvant therapies at an early stage. Since the introduction of the SLN procedure in 1993 in our institution, we have performed more than 450 selective SLN dissections, all according to the same protocol. It is important to know whether this procedure is accurate in relation to detecting the proper sentinel node and to determine the clinical outcome of this procedure after long-term follow-up. The aim of this prospective study was to investigate the accuracy of the SLN procedure and the clinical outcome of stage I or II melanoma patients who underwent selective SLN dissection after a follow-up of at least 60 months. Furthermore, factors that have an association with survival were analyzed using the Cox proportional hazards regression model.
Patients From August 1993 to December 1996, 209 consecutive patients with clinical stage I or II cutaneous melanoma as defined by the American Joint Committee on Cancer and with a Breslow thickness of  0.5 mm underwent SLN mapping and selective complete LND in a prospective study.11 The selective SLN dissection has become the standard procedure in our hospital for cutaneous melanoma and is offered to all patients. Patients were informed about the possible alternatives for treating the regional lymph nodes. All patients were treated according to the same protocol. Before the SLN procedure, the pathologic characteristics of the primary melanoma were reviewed in our hospital if the patient was referred from another institution. Patient characteristics are listed in Table 1 .
Triple Technique To identify and retrieve the SLN, the triple technique was used, as described previously.12–14 Briefly, the day before surgery, a dynamic and static lymphoscintigraphy was made using 1.0 mCi of technetium-99m–labeled colloidal albumin (Nanocoll; Sorin Biomedica, Salugia, Italy). A handheld gamma detection probe (C-trak; Care Wise Medical Products, Morgan Hill, CA; or CTC-4; Radiation Monitoring Devices, Watertown, MA) was used to verify the site of the SLNs. Shortly before surgery, 0.15 to 0.5 mL Patent Blue V (Laboratoire Guerbet, Aulnay-sous-Bois, France) was injected intradermally next to the initial site of the melanoma. A sterile-packed gamma probe was used to localize the site of incision. The blue dye and gamma probe helped to localize the SLN(s) during meticulous dissection. A lymph node was considered an SLN during surgery when it stained blue, had an in situ radioactivity count of at least three times that of the background count, or had an ex vivo radioactivity count of at least 10 times greater than that of the background count.15,16 Residual lymph nodes were excised if they contained radioactivity greater than 10% of the SLN.17 Cautious palpation of the lymph node basin was performed to detect enlarged or pathologic nonsentinel lymph nodes. Harvested SLN(s) were step-sectioned (five levels in total; 250 µm between levels) and stained with hematoxylin and eosin and immunohistochemical with S100 and HMB45.18 If the SLN contained metastatic tumor cells, a completion regional lymphadenectomy was performed at a later date. From the regional lymph basin dissection specimens, all lymph nodes were recovered. From these lymph nodes, one section was cut and stained with hematoxylin and eosin. Follow-up comprised regular outpatient physical examination at 3- to 6-month intervals. No patient was lost to follow-up. The median follow-up time was 72 months (range, 60 to 100 months).
Statistical Analysis All statistical analyses were performed with Statistical Package for the Social Sciences software for Windows 98 (SPSS, Chicago, IL).
SLN Identification In 209 patients, 242 lymph node basins were mapped. Focal accumulation in at least one basin was observed in 100% of the cases. In 176 patients (84%), lymphatic mapping of one lymph node basin was performed, and 33 patients (16%) underwent mapping of two lymph node basins. All removed SLNs (n = 378; 100%) were hot, and of these, 329 SLNs (87%) were both hot and blue. Of the 49 SLNs that were only hot, four (8%) contained metastatic disease. In two patients this was the only SLN to be tumor-positive; the two other patients also had a second positive SLN that was both hot and blue. During surgery, the SLN was found high in the left axilla in one patient and was not accessible for removal. The decision was made not to remove this SLN to avoid potential morbidity associated with the intervention. This patient had a superficial spreading melanoma on the left forearm with a Breslow thickness of 1.28 mm. He remained disease-free after a follow-up period of 67 months. Therefore, the success rate was 99.5% (208 of 209 patients).
SLN Status
The distribution of positive SLNs according to Breslow thickness is shown in Table 2 . With increasing Breslow thickness, a growing percentage of SLN-positive patients is revealed. For patients with a Breslow thickness between 0.5 and 1.0 mm, 6% of patients had a positive SLN. This increased to 55% SLN positivity in patients with a Breslow thickness of greater than 4.0 mm.
A total of 38 completion lymphadenectomies were performed in 40 patients who had at least one positive SLN. Two patients refused to undergo a completion lymphadenectomy. In 29 of these patients (76%), no additional positive lymph nodes were revealed. In the remaining nine completion lymphadenectomy specimens, additional positive lymph nodes were found. One additional positive lymph node was found in six patients, two additional positive lymph nodes were found in two patients, and three additional positive lymph nodes were found in one patient.
First Site of Recurrence
DFS and OS To date, after a median follow-up period of 72 months, 83% of the patients (174 of 209) patients are alive, six of whom have evidence of disease. During follow-up, 31 patients (15%) died of disease. Of these patients, 16 had a negative SLN (10%; 16 of 168) and 15 had a positive SLN (38%; 15 of 40) (Table 3  ). Four patients with no recurrence of disease died from another cause during follow-up.
The 5-year DFS and OS rates for the whole group were 80% and 87%, respectively (Fig 2
Figure 4 shows the OS according to the number of involved lymph nodes. Five-year OS was 79% for patients with one involved lymph node (N1 stage; ie, the SLN) and 50% for patients with two to three (N2 stage) or four (N3 stage; one patient) (P < .0001); 5-year DFS was 62% and 31%, respectively (P < .0001). All 5-year DFS and OS rates in relation to other factors are listed in Table 5.
Most remarkable, of the patients with lymphatic invasion, 87% (14 of 16) developed a relapse, and 51% of patients with ulceration present in the primary melanoma had a recurrence within 5 years after the SLN procedure (Table 5 ). Five-year OS rates for patients with ulceration or lymphatic invasion present in the primary tumor were 71% and 43%, respectively (Fig 5A and 5B).
Survival by Breslow Thickness All patients with a Breslow thickness between 0.5 and 1.0 mm remained alive during follow-up. The 5-year OS rate decreased to 63% for patients with a Breslow thickness of greater than 4.0 mm (Fig 6 ; Table 4). The OS curves for Breslow thickness according to SLN status are given in Fig 7. Five-year OS rates for SLN-negative patients per Breslow category were as follows: 100% (0.5 to 1.0 mm), 95% (1.01 to 2.0 mm), 76% (2.01 to 4.0 mm), and 60% (> 4.0 mm) (P = .0002). For SLN-positive patients, 5-year OS rates per Breslow category were as follows: 100%, 87%, 40%, and 67%, respectively (P = .02). Combination of these two factors, as shown in Fig 7, gives a helpful tool to estimate survival. Patients with a positive SLN and a Breslow thickness between 1.01 and 2.0 tend to have a better OS compared with patients with a negative SLN and a Breslow thickness exceeding 2.0 mm (P = .16).
Univariate and Multivariate Regression Analysis of DFS and OS We performed a univariate and a multivariate Cox regression analysis on all patients to determine the influence of several factors on DFS and OS (Table 6 ). The model selected for multivariate regression was created by the backward stepwise elimination method. After univariate analysis, four factors were significantly related to DFS and OS: Breslow thickness, SLN status, ulceration, and lymphatic invasion. These factors entered the multivariate analyses and all four factors had an independent and significant correlation with DFS (Table 6). Lymphatic invasion was the strongest factor, followed by ulceration, SLN status, and Breslow thickness. The factors that were independently and significantly related to a poorer OS included increasing tumor thickness (P = .002), a positive SLN (P = .002), and the presence of lymphatic invasion (P = .0009). Surprisingly, in this study ulceration was not an independent factor that was correlated with OS.
We have been performing the triple-technique SLN procedure as standard care in clinically stage I or II cutaneous melanoma patients for almost 9 years. The major reason for using this procedure is to stage patients more accurately and remove potential micrometastatic disease at an early stage while also sparing patients with a negative SLN from having to undergo a regional LND with associated morbidity. After a follow-up period of at least 60 months, we can now describe the clinical outcome of these patients more accurately. Our success rate of 99.5% in retrieving the SLN compares favorably with other series.19,20 The SLN was not removed during surgery in only one patient, although in this patient the SLN could be detected both on the lymphoscintigraphy and with the gamma probe. Removing this SLN would cause significant additional morbidity, and the decision was made to leave the SLN in situ. The false-negative rate in this study was 9%. Four of 168 patients who initially had a negative SLN developed a recurrence in the same draining lymph node basin. Pathologic re-evaluation of the SLNs of these patients did not reveal (micro)metastatic disease. In two of these four patients, another possible reason was found to be the cause of the false-negative procedure. In one patient, the initial excision of a melanoma on the trunk had been too wide (5 x 9 cm). This excision may have changed the initial lymphatic draining pattern. In another patient, re-evaluation of the lymphoscintigraphy made during the SLN procedure showed a second lymph vessel that initially was not identified. The associated down-stream node was not removed during surgery. There are three major causes of false-negative procedures: pathologic failure, technical failure, and biologic failure.21 In the first, a histopathologic sampling error fails to detect micrometastatic disease. Using step sections of the SLN and immunohistochemistry increases the detection rate of (micro)metastases.18 A technical failure can have several causes. First, the method used to identify and retrieve the SLN is extremely important. The combined, three-pronged approach (triple technique) to detect the SLN improves the success rate and therefore results in fewer false-negative procedures. The first two mentioned false-negative procedures are results of technical failures; narrow primary excision of the melanoma and thorough interpretation of the lymphoscintigraphy are indispensable. The last two false-negative procedures are most likely the result of biologic failure. A biologic failure occurs when lymphatics are obstructed by melanoma cells, which cause a rerouting of the lymph flow. As a consequence, the true SLN is not detected and a non-SLN is retrieved. This type of failure is difficult to manage and is inevitable. Compared with other series in which false-negative rates between 5.5% and 12% are described after median follow-up periods of 14 to 35 months, a false-negative rate of 9% after a median follow-up of 72 months is, in our opinion, acceptable.20–24 Nevertheless, some of the false-negative procedures could have been prevented. The SLN procedure is a technically demanding procedure that requires considerable skill and experience not only from the operating surgeon but also from the physician performing the lymphoscintigraphy and the pathologist evaluating the SLN. In this study, 22% of the patients developed a recurrence. Of patients with a positive SLN, 55% relapsed. Recurrence was uncommon after a negative selective SLN dissection, occurring in only 14% of patients in this study after a median follow-up of 72 months. Gershenwald et al21 and Thompson25 described comparable figures after a much shorter follow-up period. On the other hand, these studies had larger sample sizes compared with that of the current study. Before the SLN era, the regional lymph nodes were the most frequent site of recurrence. The SLN procedure changed the pattern of recurrence by reducing the number of first recurrences within the regional lymph node basin.26 The most important sites for recurrences are now locoregional (53%) and systemic (38%). Whether this changed pattern of recurrence influences survival is still a matter of debate.
In this series, the 5-year DFS and OS rates were 80% and 87%, respectively. Patients with a negative SLN have a significantly better DFS and OS compared with SLN-positive patients (88% and 92% v 50% and 67%, respectively). In other series, similar percentages were found.19,27–29 Essner et al29 compared selective SLN dissection with ELND in a matched-pair analyses. DFS and OS were identical for both approaches, and they concluded that selective SLN dissection and ELND seemed to be therapeutically equivalent procedures for the management of clinically negative regional lymph nodes. They even showed that 5-year OS for patients with a positive SLN (64%) was higher compared with that of patients with tumor-positive nodal dissections after ELND (45%); the comparison approached significance (P = .077). The good survival results in our study might be because a substantial number of patients have a tumor with a thickness of less than 1.0 mm. Nevertheless, analysis of patients with a Breslow thickness of Comparable to Dessureault et al,30 we found an OS for patients with a negative SLN of 92%. They found a significantly better survival compared with patients with negative nodes after ELND (77.7%) or observation alone (69.8%) and concluded that selective SLN dissection might contribute to a survival benefit in populations of patients with melanoma. A possible reason for this better survival after negative selective SLN dissection compared with negative ELND might be the reflection of the greater accuracy of the SLN procedure to detect nodal metastases. Selective SLN dissection misses fewer patients with stage III melanoma than does ELND or observation.30 Therefore, the group of patients after negative ELND probably contains patients who might have been SLN-positive after an SLN procedure.18 Multivariate analysis of those factors that influenced DFS and OS demonstrated that Breslow thickness, SLN status, and lymphatic invasion were significantly correlated to DFS and OS. Ulceration was significantly related only to DFS. As also described by others, SLN status and Breslow thickness are strong prognostic factors to determine clinical outcome, especially OS.14,31–33 The lack of multivariate significance for ulceration as a predictor of OS is unexplained but may be an artifact of inadequate sample size or possibly due to the influence of multiple confounding covariables in this model. Cascinelli et al33 also found that ulceration was not a significant independent prognostic factor. An important finding in our study was the significantly strong and independent association of lymphatic invasion of the primary melanoma with survival. Lymphatic invasion was the strongest prognostic factor for OS after multivariate analysis (P = .0009). Borgstein et al34 and Statius Muller et al14 also showed that lymphatic invasion is a strong and relevant predictor of developing recurrence and should be included as a stratification criterion. Trial 14 of the World Health Organization Melanoma Program has indirectly outlined the potential benefit of the SLN procedure.2 In that study, patients with occult lymph node metastases discovered at ELND showed a better survival compared with patients who received therapeutic LND at the time when clinical nodal involvement appeared. Furthermore, data from another recent prospective clinical trial suggest that occult lymph node micrometastases are clinically important and early therapeutic LND may favorably impact survival.1,7 Thus selective LND is potentially therapeutic for a relatively large subset of patients. In addition to this possible potential therapeutic effect, lymphatic mapping and selective SLN dissection have some major advantages. First and foremost, the detection of micrometastatic disease using the SLN procedure allows a more accurate staging. SLN status is a significantly strong and independent prognostic factor. Second, the SLN procedure potentially spares node-negative patients from further lymph node dissection associated with significant morbidity. Third, it provides a consistent interpretation of clinical trials when true pathologic stage is known. Fourth, it provides a tool to select patients for adjuvant therapy trials. Fifth, a more accurate knowledge of lymphatic drainage patterns is provided by the SLN procedure. Finally, there is an important psychologic benefit for patients whose SLN does not reveal metastases. Although survival of patients with a Breslow thickness of less than 1.0 mm is 100% in our study, this psychologic benefit is still a reason to perform an SLN procedure in these patients, although the application of an SLN procedure in this group of patients is questionable.35 We conclude that the triple-technique SLN procedure, with a success rate of 99.5% and a false-negative rate of 9% after a median follow-up of 72 months, is an accurate and reliable procedure. A 5-year OS rate of 87%, with 92% for patients with a negative SLN and 67% for patients with a positive SLN, is promising. SLN status, Breslow thickness, and lymphatic invasion are strong predictors for survival. Nevertheless, whether the SLN procedure indeed improves survival is difficult to conclude from this study, moreover because this is a nonrandomized trial with no control arm. It is hoped that the outcome of the Multicenter Selective Lymphadenectomy Trial, in which selective SLN dissection and selective complete LND are compared with observation, will provide conclusive evidence of the impact of selective LND on OS.20 While we await the results of this study, we believe that even if selective SLN dissection in and of itself does not improve survival, it is of great value and should be continued until or unless another less invasive staging test with similar predictive value is developed.
Supported by a grant from the Fritz Ahlqvist Foundation, Aerdenhout, The Netherlands.
1. Balch CM, Soong SJ, Bartolucci AA, et al: Efficacy of an elective regional lymph node dissection of 1 to 4 mm thick melanomas for patients 60 years of age and younger. Ann Surg 224:255–263, 1996[CrossRef][Medline] 2. Cascinelli N, Morabito A, Santinami M, et al: Immediate or delayed dissection of regional nodes in patients with melanoma of the trunk: A randomised trial — WHO Melanoma Programme. Lancet 351:793–796, 1998[CrossRef][Medline] 3. Drepper H, Kohler CO, Bastian B, et al: Benefit of elective lymph node dissection in subgroups of melanoma patients: Results of a multicenter study of 3616 patients. Cancer 72:741–749, 1993[CrossRef][Medline] 4. Sim FH, Nelson TE, Pritchard DJ: Malignant melanoma: Mayo Clinic experience. Mayo Clin Proc 72:565–569, 1997[Medline] 5. Veronesi U, Adamus J, Bandiera DC, et al: Delayed regional lymph node dissection in stage I melanoma of the skin of the lower extremities. Cancer 49:2420–2430, 1982[CrossRef][Medline] 6. Sim FH, Taylor WF, Ivins JC, et al: A prospective randomized study of the efficacy of routine elective lymphadenectomy in management of malignant melanoma: Preliminary results. Cancer 41:948–956, 1978[CrossRef][Medline] 7. Balch CM, Soong S, Ross MI, et al: Long-term results of a multi-institutional randomized trial comparing prognostic factors and surgical results for intermediate thickness melanomas (1.0 to 4.0 mm). Intergroup Melanoma Surgical Trial. Ann Surg Oncol 7:87–97, 2000[Abstract] 8. Morton DL, Wen DR, Wong JH, et al: Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 127:392–399, 1992[Abstract] 9. Reintgen D, Cruse CW, Wells K, et al: The orderly progression of melanoma nodal metastases. Ann Surg 220:759–767, 1994[Medline] 10. Thompson JF, McCarthy WH, Bosch CM, et al: Sentinel lymph node status as an indicator of the presence of metastatic melanoma in regional lymph nodes. Melanoma Res 5:255–260, 1995[Medline]
11. Balch CM, Buzaid AC, Soong SJ, et al: Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol 19:3635–3648, 2001 12. Statius Muller MG, Borgstein PJ, Pijpers R, et al: Reliability of the sentinel node procedure in melanoma patients: Analysis of failures after long-term follow-up. Ann Surg Oncol 7:461–468, 2000[Abstract] 13. Veen Hvd, Hoekstra OS, Paul MA, et al: Gamma probe-guided sentinel node biopsy to select patients with melanoma for lymphadenectomy. Br J Surg 81:1769–1770, 1994[Medline] 14. Statius Muller MG, van Leeuwen PA, de Lange-De Klerk ES, et al: The sentinel lymph node status is an important factor for predicting clinical outcome in patients with stage I or II cutaneous melanoma. Cancer 91:2401–2408, 2001[CrossRef][Medline] 15. Albertini JJ, Cruse CW, Rapaport D, et al: Intraoperative radio-lympho-scintigraphy improves sentinel lymph node identification for patients with melanoma. Ann Surg 223:217–224, 1996[CrossRef][Medline] 16. Alex JC, Weaver DL, Fairbank JT, et al: Gamma-probe-guided lymph node localization in malignant melanoma. Surg Oncol 2:303–308, 1993[Medline]
17. McMasters KM, Reintgen DS, Ross MI, et al: Sentinel lymph node biopsy for melanoma: How many radioactive nodes should be removed? Ann Surg Oncol 8:192–197, 2001 18. Diest PJv, Peterse HL, Borgstein PJ, et al: Pathological investigation of sentinel lymph nodes. Eur J Nucl Med 26:S43–S49, 1999 (suppl)[CrossRef][Medline]
19. Gershenwald JE, Thompson W, Mansfield PF, et al: Multi-institutional melanoma lymphatic mapping experience: The prognostic value of sentinel lymph node status in 612 stage I or II melanoma patients. J Clin Oncol 17:976–983, 1999 20. Morton DL, Thompson JF, Essner R, et al: Validation of the accuracy of intraoperative lymphatic mapping and sentinel lymphadenectomy for early-stage melanoma: A multicenter trial —Multicenter Selective Lymphadenectomy Trial Group. Ann Surg 230:453–463, 1999[CrossRef][Medline] 21. 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 16:2253–2260, 1998[Abstract] 22. Wagner JD, Corbett L, Park HM, et al: Sentinel lymph node biopsy for melanoma: Experience with 234 consecutive procedures. Plast Reconstr Surg 105:1956–1966, 2000[Medline] 23. Jansen L, Nieweg OE, Peterse JL, et al: Reliability of sentinel lymph node biopsy for staging melanoma. Br J Surg 87:484–489, 2000[CrossRef][Medline] 24. Nguyen CL, McClay EF, Cole DJ, et al: Melanoma thickness and histology predict sentinel lymph node status. Am J Surg 181:8–11, 2001[CrossRef][Medline] 25. Thompson JF: The Sydney Melanoma Unit experience of sentinel lymphadenectomy for melanoma. Ann Surg Oncol 8:44S–47S, 2001 (suppl)[Medline] 26. Statius Muller MG, van Leeuwen PAM, van Diest PJ, et al: Pattern and incidence of first site recurrences following sentinel node procedure in melanoma patients. World J Surg 26:1405–1411, 2002[CrossRef][Medline] 27. Essner R, Rose M, Kojima M, et al: Predicting the natural history of melanoma after tumor-negative sentinel lymph node dissection. Proc Am Soc Clin Oncol 20:xxx, 2001 (abstr 1397) 28. Cascinelli N, Belli F, Santinami M, et al: Sentinel lymph node biopsy in cutaneous melanoma: The WHO Melanoma Program experience. Ann Surg Oncol 7:469–474, 2000[Abstract] 29. Essner R, Conforti A, Kelley MC, et al: Efficacy of lymphatic mapping, sentinel lymphadenectomy, and selective complete lymph node dissection as a therapeutic procedure for early- stage melanoma. Ann Surg Oncol 6:442–449, 1999[Abstract]
30. 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 8:766–770, 2001 31. Marghoob AA, Koenig K, Bittencourt FV, et al: Breslow thickness and Clark level in melanoma: Support for including level in pathology reports and in American Joint Committee on Cancer Staging. Cancer 88:589–595, 2000[CrossRef][Medline]
32. Balch CM, Soong SJ, Gershenwald JE, et al: Prognostic factors analysis of 17,600 melanoma patients: Validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol 19:3622–3634, 2001 33. Cascinelli N, Clemente C, Bifulco C, et al: Do patients with tumor-positive sentinel nodes constitute a homogeneous group? Ann Surg Oncol 8:35S–37S, 2001 (suppl)[Medline] 34. Borgstein PJ, Meijer S, van Diest PJ: Are locoregional cutaneous metastases in melanoma predictable? Ann Surg Oncol 6:315–321, 1999[Abstract]
35. McMasters KM, Reintgen DS, Ross MI, et al: Sentinel lymph node biopsy for melanoma: Controversy despite widespread agreement. J Clin Oncol 19:2851–2855, 2001 Submitted July 29, 2002; accepted November 25, 2002. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
1.00 mm survived, and SLN-positive patients with a Breslow thickness less than 2.00 mm tend to have a better prognosis compared with SLN-negative patients with a Breslow thickness greater than 2.00 mm. SLN status (P = .002), Breslow thickness (P = .002), and lymphatic invasion (P = .0009) were all found to be independent prognostic factors for overall survival. 
2 test to compare the result of a specific subgroup with that of the rest of the patient population. Analysis of disease-free survival (DFS) and overall survival (OS) was performed using the Kaplan-Meier approach, with statistical analysis performed using the log-rank test. Univariate and multivariate analyses on the basis of Cox’s proportional hazards regression model were used to associate covariates to DFS and OS. Breslow thickness was treated as a continuous variable for both univariate and multivariate analyses. P values of less than .05 were considered significant. 
