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© 1999 American Society for Clinical Oncology Multi-Institutional Melanoma Lymphatic Mapping Experience: The Prognostic Value of Sentinel Lymph Node Status in 612 Stage I or II Melanoma PatientsFrom the Departments of Surgical Oncology, Pathology, and Biomathematics, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and the Cutaneous Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL. Address reprint requests to Merrick I. Ross, MD, Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 106, Houston, TX 77030.
PURPOSE: To compare the effect of pathologic sentinel lymph node (SLN) status with that of other known prognostic factors on recurrence and survival in patients with stage I or II cutaneous melanoma. PATIENTS AND METHODS: We reviewed the records of 612 patients with primary cutaneous melanoma who underwent lymphatic mapping and SLN biopsy between January 1991 and May 1995 to determine the effects of tumor thickness, ulceration, Clark level, location, sex, and SLN pathologic status on disease-free and disease-specific survival. RESULTS: In the 580 patients in whom lymphatic mapping and SLN biopsy were successful, the SLN was positive by conventional histology in 85 patients (15%) but negative in 495 patients (85%). SLN status was the most significant prognostic factor with respect to disease-free and disease-specific survival by univariate and multiple covariate analyses. Although tumor thickness and ulceration influenced survival in SLN-negative patients, they provided no additional prognostic information in SLN-positive patients. CONCLUSION: Lymphatic mapping and SLN biopsy is highly accurate in staging nodal basins at risk for regional metastases in primary melanoma patients and identifies those who may benefit from earlier lymphadenectomy. Furthermore, pathologic status of the SLN in these patients with clinically negative nodes is the most important prognostic factor for recurrence. The information from SLN biopsy is particularly helpful in establishing stratification criteria for future adjuvant trials.
IT IS ESTIMATED that at least 41,600 new cases of invasive melanoma will be diagnosed in 1998 in the United States alone, representing a 52% increase since 1989.1,2 Although most of these patients present with clinically negative nodal basins, many of them actually harbor occult regional lymph node metastases. As a result, the optimal scope of surgical management has remained a controversial issue. Although several retrospective reports have demonstrated a survival benefit for patients who underwent elective lymph node dissection (ELND),3-8 only subsets of patients in one prospective, randomized trial had a demonstrated survival benefit from ELND.9-11 We and others have used lymphatic mapping and sentinel lymph node (SLN) biopsy as a way to identify regional nodal metastases and determine which patients require lymphadenectomy (ie, selective lymphadenectomy). Although initially SLNs were identified in approximately 80% of patients who underwent the procedure,12 current rates approach 100% because of improvements in preoperative lymphoscintigraphy and intraoperative mapping techniques, including use of combined modality intraoperative SLN localization, which utilizes both dye and radiolabeled colloid.13-18 This approach accurately stages the regional nodal basin. The immediate false-negative rate, defined as the percentage of nodal basins that harbor nodal metastases in nodes other than the SLN as determined by synchronous ELND after a negative SLN biopsy, has been reported to be less than 4% in several studies.12,13,15,19 However, the prognostic significance of SLN status has not been previously described. For this study, we postulated that SLN status is the most important of the known prognostic factors and tested this idea in a large series of patients with stage I or II melanoma treated consecutively at two cancer centers.
Patients From January 1991 to May 1995, 612 patients with primary cutaneous melanoma underwent lymphatic mapping and SLN biopsy at the University of Texas M.D. Anderson Cancer Center (n = 314) and the H. Lee Moffitt Cancer Center (n = 298). These procedures are part of current practice guidelines at both institutions. All patients diagnosed with primary cutaneous melanoma underwent the procedure if the tumor was at least 1.0 mm thick or, if less than 1.0 mm, it was at least Clark level IV or ulcerated, and there was no evidence of metastatic melanoma in regional lymph nodes and distant sites by physical examination and staging evaluation (chest x-ray and alkaline phosphatase and lactate dehydrogenase levels). Several known prognostic patient and primary tumor factors (age, sex, tumor thickness, Clark level, axial location, and presence of ulceration), as well as pathologic status of the SLN, were documented for each patient.
SLN Mapping Technique Generally, excised SLNs were analyzed by conventional histologic staining (hematoxylin and eosin) of bisected specimens. In some cases, immunohistochemical staining was performed using antisera to the S-100 protein and the melanoma antigen HMB-45 to clarify equivocal findings. Early in our experience with lymphatic mapping, patients underwent planned synchronous ELND after a negative SLN biopsy; subsequently, patients underwent no immediate further surgical therapy if the pathology of the SLN was negative. Those patients in whom lymph nodes contained evidence of metastatic melanoma underwent therapeutic lymphadenectomy of the affected basins. Patients with a positive SLN were not routinely offered adjuvant therapy, because no standard treatment was available during the study period. However, patients were offered participation in prospective clinical trials evaluating adjuvant therapy regimens. Accrual data from one institution (M.D. Anderson) were collected. Postoperative follow-up consisted of physical examination, chest x-ray, and determinations of serum alkaline phosphatase and lactate dehydrogenase levels. Further investigations, including computed tomography, magnetic resonance imaging, and/or nuclear scan, were also performed selectively to confirm abnormal findings suggestive of metastatic melanoma. Routine surveillance was recommended every 3 to 4 months for the first 2 years, every 6 months for years 3 to 5, and annually thereafter. Patient charts (at M.D. Anderson) and a prospective melanoma database (at H. Lee Moffitt) were reviewed to determine relevant clinical information and to identify sites of recurrence. Disease-free survival and time to most recent follow-up (or death) were calculated from the date of primary melanoma diagnosis.
Statistical Analysis Multiple covariate analyses used to associate covariates to timed-event end points such as disease-free and disease-specific survival were performed using the Cox proportional hazards regression model. Tumor thickness was treated as a continuous variable for both univariate and multiple covariate analyses. The Spearman rank correlation analysis was performed for all seven covariates (age, sex, tumor thickness, Clark level, axial location, ulceration, and SLN status). Correlation analyses were also performed between regression coefficients obtained from the Cox proportional hazards regression model.
Distribution of Mapped Basins Six hundred eighty-three lymph node basins were mapped in 612 patients. Axillary, inguinal, and cervical nodal basins comprised 59%, 30%, and 11% of the total basins evaluated, respectively. Five hundred forty-five patients (89%) underwent lymphatic mapping of one regional nodal basin, 63 patients (10%) underwent synchronous lymphatic mapping of two regional nodal basins, and four patients (1%) underwent synchronous lymphatic mapping of three regional nodal basins. Basins were distributed equally between the left and right sides.
SLN Identification Rate
Of the 612 patients who underwent lymphatic mapping and attempted SLN biopsy, at least one SLN was identified in 580 patients (95%) (Fig 1). The most common reason for failure (n = 32) to proceed from lymphatic mapping to successful SLN biopsy was the inability to observe concentrated dye within a node (67%). There was no significant difference in prognostic factors between this group and the group in which SLNs were successfully mapped and biopsied (data not shown).
Histologic Status of SLN Four hundred ninety-five patients (85%) who underwent successful lymphatic mapping and SLN biopsy had a negative SLN (Fig 1). As part of our early experience with lymphatic mapping, 72 patients (15% of negative SLN biopsies) underwent planned synchronous ELND after a negative SLN biopsy; in only one patient did a nonsentinel lymph node demonstrate evidence of metastatic melanoma (negative predictive value = 98.6%).
SLN status stratified by tumor thickness is presented in Table 2. The frequency of a positive SLN biopsy increased as tumor thickness increased and ranged from 4.8% in patients with tumors
Histologic Analysis of Lymphadenectomy Specimens After Positive SLN Biopsy
Patient Characteristics, Prognostic Factors, and Adjuvant Therapy
The distribution of prognostic factors grouped by histologic status of the SLN is illustrated in Table 4. Patients with a positive SLN were statistically more likely to have primary tumors that were thick, axially located, or ulcerated. Patient age, sex, and Clark level were not significantly different between SLN groups. In patients with at least one positive SLN, 50% received no adjuvant therapy and 50% received adjuvant therapy: interferon, 40%; vaccine, 5%; and biochemotherapy, 5%.
Survival Analysis
The results of univariate analyses of several known prognostic factors with respect to disease-free survival are shown in Table 5. Positive SLN status, tumor thickness, Clark level greater than III, and presence of ulceration were all statistically significant prognostic factors by univariate analysis. The 3-year disease-free survival for negative and positive SLN patients was 88.5% and 55.8%, respectively (P < .0001) (Fig 3A). Although tumor thickness, Clark level greater than III, presence of ulceration, and a positive SLN remained significant by multiple covariate analysis, SLN status was the strongest predictor.
Univariate analyses of the several known prognostic factors with respect to disease-specific survival are also presented in Table 5. The same four factors were again statistically significant. The 3-year disease-specific survival for negative and positive SLN patients was 96.8% and 69.9%, respectively (P < .0001) (Fig 3B). Positive SLN status, Clark level greater than III, and tumor thickness remained significant by multiple covariate analysis. However, positive SLN status remained the strongest predictor (Table 5). Correlation analyses were performed. No significant correlation between any of the seven covariates was identified using the Spearman rank correlation. In addition, there was no significant correlation between the regression coefficients obtained from the Cox proportional hazards regression model.
Survival Analysis According to Pathologic SLN Status
Univariate and multiple covariate analyses of several known prognostic factors with respect to disease-specific survival in patients with a pathologically negative SLN are also shown in Table 6. Tumor thickness, presence of ulceration, and Clark level greater than III were all statistically significant prognostic factors by univariate analysis. Tumor thickness and presence of ulceration remained significant by multiple covariate analysis. However, tumor thickness remained the strongest predictor. In patients with at least one positive SLN, univariate analyses of these prognostic factors with respect to disease-free or disease-specific survival demonstrated that only tumor thickness was statistically significant (disease-free survival only, P = .027). However, no prognostic factor was significant by multiple covariate analysis with respect to either disease-free or disease-specific survival.
Evidence for Technique's Accuracy The technique of lymphatic mapping and SLN biopsy has gained increasing attention since its initial description by Morton et al.12 It is a minimally invasive method of identifying those primary melanoma patients who may be harboring clinically occult nodal metastases. The technique is based on the now well-supported hypothesis that melanoma lymphatic metastases follow an orderly progression through afferent lymphatic channels to SLNs before spreading into other regional, nonsentinel lymph nodes.13 The current study supports this hypothesis: (1) only one (1.4%) of 72 patients who underwent complete lymphadenectomy after negative SLN biopsy had evidence of micrometastatic disease in a nonsentinel lymph node; (2) the SLNs were the only positive lymph nodes in 79% of patients with at least one positive SLN; and (3) 80% of the SLNs removed from patients with at least one positive lymph node contained evidence of metastatic disease, whereas only 2% of nonsentinel lymph nodes obtained by completion therapeutic lymphadenectomy from these patients contained histologic evidence of disease.
The overall SLN identification rate of 95% in this study includes patients mapped over a 4
Comparability With Other Studies The survival analysis shows that the natural history of our patient population matches well with other series.23,24 Recently, Balch et al9 reported that at least 60% of first distant recurrences observed in a large prospective trial occurred within the same approximate follow-up period as in this study, in a patient population that had a median tumor thickness (1.8 mm) identical to that in this study. Thus, the majority of all recurrences in the current study should have already occurred by the time of this analysis.
Prognostic Significance Careful scrutiny of these multiple covariate analyses reveals that although tumor thickness (treated as a continuous variable) was a statistically significant prognostic factor, the magnitude of this effect was notably small, as demonstrated by a hazards ratio of 1.23 (for disease-specific survival), compared with 6.53 for the presence of a positive SLN. Furthermore, application of the hazards ratio for tumor thickness reveals that, compared with a 1-mm primary melanoma, a 5-mm tumor carries a hazards ratio of (1.23)4 = 2.29, still notably lower than that for a positive SLN. Historically, tumor thickness has been the most used prognostic factor in patients with stage I and II disease. In an attempt to more specifically address the role of this and other prognostic factors in patients undergoing SLN biopsy, we evaluated disease-free and disease-specific survival by stratifying patients with respect to pathologic SLN status. Univariate and multiple covariate analyses revealed that tumor thickness and ulceration were important prognostic discriminators in patients with a negative SLN. In contrast, for patients with a positive SLN, neither tumor thickness nor any other factor provided additional prognostic information. Taken together, these data further support our postulate that the presence of a histologically positive SLN best predicts recurrence and survival in patients with clinically node-negative cutaneous melanoma. In SLN-negative patients, the combination of SLN status and either tumor thickness or ulceration therefore demonstrates prognostic synergy when disease-free and disease-specific survival are assessed. In these patients, increasing primary tumor thickness or presence of ulceration may be predictive for other molecular events (eg, angiogenesis) that ultimately affect recurrence and survival. Additionally, we have recently reported that the use of standard histologic techniques may not detect clinically relevant occult metastatic melanoma in the SLNs of some patients17; a subset of SLN-negative patients may therefore be understaged, suggesting that differences observed between SLN-negative and SLN-positive patients may be underestimated.
Advantages to Patients The selective approach afforded by SLN biopsy identifies those patients requiring complete node dissection, minimizes surgery-related morbidity for patients without metastases, and provides critical and accurate staging information. In theory, SLN biopsy can provide even more accurate staging information, since the limited pathologic specimen permits the opportunity to more completely assess these select lymph nodes most likely to contain metastases by more specialized pathologic techniques.17 The demonstration in a prospective, randomized, controlled clinical trial26 that interferon alfa-2b produces a survival advantage for the high-risk melanoma patient provides an additional important motivation for assessment of the regional nodal basin, as the benefit from this form of adjuvant therapy was most pronounced for node-positive patients. Lymphatic mapping and SLN biopsy offers a minimally invasive method of identifying those patients who actually have stage III disease, who are most likely to relapse at distant sites, and who may therefore benefit from this or other forms of adjuvant therapy. The benefits of this technique are not, however, limited only to those patients with a positive SLN. Importantly, those with a negative SLN comprise a favorable patient group with significantly less risk for recurrence. Since no benefit from adjuvant therapy has been demonstrated for histologically node-negative patients, they may be spared the morbidity and cost of additional therapy or may be entered onto trials evaluating less aggressive adjuvant approaches. Low-dose interferon regimens have recently been evaluated in clinically node-negative patients with primary tumors at least 1.5 mm thick.27,28 Preliminary reports from these randomized trials demonstrate a disease-free survival benefit for patients receiving this regimen. Although these data are promising, the lack of histologic evaluation of the regional lymph nodes makes it unclear which histologic subgroups truly benefit. SLN biopsy should therefore be considered in the design of future prospective randomized trials evaluating adjuvant therapy in the clinically node-negative patient to better stratify patients into prognostically homogeneous groups.
We thank Walter J. Pagel of the Department of Scientific Publications, the University of Texas M.D. Anderson Cancer Center, for editorial assistance.
Presented at the 49th Annual Meeting of the Society of Surgical Oncology, Atlanta, GA, March 1996.
1. Landis SH, Murray T, Bolden S, et al: Cancer statistics, 1998. CA Cancer J Clin 48:6-29, 1998[Abstract]
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Silverberg E, Lubera JA: Cancer statistics, 1989. CA Cancer J Clin 39:3-20, 1989 3. Balch CM, Soong S-J, Milton GW, et al: A comparison of prognostic factors and surgical results in 1,786 patients with localized (stage I) melanoma treated in Alabama, USA, and New South Wales, Australia. Ann Surg 196:677-684, 1982[Medline] 4. Drepper H, Kohler CO, Bastian B, et al: Benefit of elective lymph node dissection in subgroups of melanoma patients. Cancer 72:741-749, 1993[Medline] 5. McCarthy WH, Shaw HM, Milton GW: Efficacy of elective lymph node dissection in 2,347 patients with clinical stage I malignant melanoma. Surg Gynecol Obstet 161:575-580, 1985[Medline] 6. Rompel R, Garbe C, Buttner P, et al: Elective lymph node dissection in primary malignant melanoma: A matched-pair analysis. Melanoma Res 5:189-194, 1995[Medline] 7. Wanebo HJ, Woodruff J, Fortner JG: Malignant melanoma of the extremities: A clinicopathologic study using levels of invasion (microstage). Cancer 35:666-676, 1975[Medline] 8. Reintgen DS, Cox EB, McCarty KS Jret al: Efficacy of elective lymph node dissection in patients with intermediate thickness primary melanoma. Ann Surg 198:379-385, 1983[Medline] 9. Balch CM, Soong S-J, 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 224:255-266, 1996[Medline] 10. Veronesi U, Adamus J, Bandiera DC, et al: Inefficacy of immediate node dissection in stage I melanoma of the limbs. N Engl J Med 297:627-630, 1977[Abstract] 11. Sim FH, Taylor WF, Pritchard DJ, et al: Lymphadenectomy in the management of stage I malignant melanoma: A prospective randomized study. Mayo Clin Proc 61:697-705, 1986[Medline] 12. Morton DL, Wen D-R, Wong JH, et al: Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 127:392-399, 1992[Abstract] 13. Reintgen D, Cruse CW, Berman C, et al: The orderly progression of melanoma nodal metastases. Ann Surg 220:759-767, 1994[Medline] 14. Albertini JJ, Cruse CW, Rapaport D, et al: Intraoperative radiolymphoscintigraphy improves sentinel lymph node identification for patients with melanoma. Ann Surg 223:217-224, 1996[Medline] 15. Thompson JF, McCarthy WH, Bosch CMJ, 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] 16. Gershenwald JE, Colome MI, Thompson W, 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] 17. Gershenwald JE, Tseng C-et al: Improved sentinel lymph node localization in primary melanoma patients with the use of radiolabeled colloid. Surgery 124:203-210, 1998[Medline] 18. Krag DN, Meijer SJ, Weaver DL, et al: Minimal-access surgery for staging of melanoma. Arch Surg 130:654-658, 1995[Abstract] 19. Uren RF, Howman-Giles R, Thompson JF, et al: Lymphoscintigraphy to identify sentinel lymph nodes in patients with melanoma. Melanoma Res 4:395-399, 1994[Medline] 20. Balch CM, Urist MM, Karakousis CP, et al: Efficacy of 2-cm surgical margins for intermediate-thickness melanomas (1 to 4 mm): Results of a multi-institutional randomized surgical trial. Ann Surg 218:262-267, 1993[Medline] 21. Veronesi U, Cascinelli N: Narrow excision (1-cm margin): A safe procedure for thin cutaneous melanoma. Arch Surg 126:438-441, 1991[Abstract] 22. Slingluff CL, Stidham KR, Ricci WM, et al: Surgical management of regional lymph nodes in patients with melanoma: Experience with 4682 patients. Ann Surg 219:120-130, 1994[Medline] 23. McCarthy WH, Shaw HM, Thompson JF, et al: Time and frequency of recurrence of cutaneous stage I malignant melanoma with guidelines for follow-up study. Surg Gynecol Obstet 166:497-502, 1988[Medline] 24. Soong S-J, Shaw HM, Balch CM, et al: Predicting survival and recurrence in localized melanoma: A multivariate approach. World J Surg 16:191-195, 1992[Medline] 25. Cascinelli N, Morabito A, Santinami M, et al: Immediate or delayed dissection of regional nodes in patients with melanoma of the trunk: A randomized trial—WHO Melanoma Programme. Lancet 14:793-796, 1998 26. 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 14:7-17, 1996[Abstract] 27. Grob JJ, Dreno B, de la Salmoniere P, et al: Randomised trial of interferon alfa-2a as adjuvant therapy in resected primary melanoma thicker than 1.5 mm without clinically detectable node metastases: French Cooperative Group on Melanoma. Lancet 351:1905-1910, 1998[Medline]
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Pehamberger H, Soyer HP, Steiner A, et al: Adjuvant interferon alfa-2a treatment in resected primary stage II cutaneous melanoma: Austrian Malignant Melanoma Cooperative Group. J Clin Oncol 16:1425-1429, 1998 Submitted September 30, 1997; accepted November 16, 1998. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
2 test and continuous data by Student's t test or Wilcoxon rank-sum test whenever appropriate. Tumor thickness was grouped by American Joint Committee on Cancer criteria to analyze the percentage of SLNs that were positive when patients were stratified by this prognostic factor. Disease recurrence and survival curves were constructed using the Kaplan-Meier product-limit method and were analyzed by the log-rank procedure. The ticks along the curves in the Kaplan-Meier survival plots represent censored observations. 
1.50 mm to 34.4% in those patients with tumors thicker than 4.00 mm (P < .00001 by 
-year period both before and after intraoperative gamma probe techniques became available. Analysis of our experience using combined modality lymphatic mapping, which incorporates the use of both isosulfan blue dye and intraoperative gamma probe localization techniques, reveals an SLN identification rate approaching 100%.
