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Annals of Surgical Oncology 8:109-115 (2001)
© 2001 Society of Surgical Oncology

ORIGINAL ARTICLES

Risk Factors for Nodal Recurrence After Lymphadenectomy for Melanoma

Ihor Pidhorecky, MD, R. Jeffrey Lee, MD, Gary Proulx, MD, Daniel R. Kollmorgen, MD, Chaoying Jia, MD, Deborah L. Driscoll, BA, William G. Kraybill, MD and John F. Gibbs, MD

From the Division of Surgical Oncology (IP, DRK, DLD, WGK, JFG) and Division of Radiation Medicine (RJL, GP, CJ), Roswell Park Cancer Institute, State University of New York, Buffalo, New York.

Correspondence: Address correspondence and reprint requests to: John F. Gibbs, MD, Division of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY 14263; Fax: 716-845-3434; E-mail: john.gibbs{at}roswellpark.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: The risk and outcome of regional failure after elective and therapeutic lymph node dissection (ELND/TLND) for microscopically and macroscopically involved lymph nodes without adjuvant radiotherapy were evaluated.

Methods: Retrospective melanoma database review of 338 patients (ELND 85, TLND 253) from 1970 to 1996 with pathologically involved lymph nodes.

Results: Regional recurrence occurred in 14% of patients treated with ELND (n = 12) and 28% of patients treated with TLND (n = 72; P = .009). Risk factors associated with nodal recurrence were advanced age, primary lesion in the head and neck region, depth of the primary lesion, number of involved lymph nodes, and extracapsular extension (ECE). For each nodal basin, the ELND group had a lower incidence of recurrence than the TLND group. The TLND group had larger lymph nodes, greater number of involved lymph nodes, and a higher incidence of ECE. The 10-year disease-specific survival was 51% vs. 30% for ELND and TLND, respectively (P = .0005). Nodal basin failure was predictive of distant metastasis, with 87% developing distant disease compared with 54% of patients without nodal recurrence (P < .0001). Of six patients who underwent a second dissection after isolated nodal recurrence, five patients have had a median disease-free interval of 79 months.

Conclusions: After ELND or TLND, patients who have a large tumor burden (thick primary melanoma, multiply involved lymph nodes, ECE), advanced age, and a primary lesion located in the head and neck have a significantly increased likelihood of relapse and a decreased survival. Few patients present with an isolated nodal recurrence, but the majority can be salvaged by a second dissection.

Key Words: Melanoma • Lymph node dissection • Nodal recurrence.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Loco-regional recurrence is the most common site of failure after primary excision of cutaneous melanoma.1–4 Traditionally, the regional nodal basin that drains the site of the primary tumor has been treated selectively by lymphadenectomy with the goal of improving loco-regional control and prolonging survival. Lymphadenectomy procedures in these nodal basins have been labeled therapeutic lymph node dissection (TLND) for clinically evident disease and elective lymph node dissection (ELND) for the basin with clinically negative nodes but at high risk for metastases. Although there is no controversy with the surgical resection of obviously involved lymph nodes, dissection of regional nodes in those patients without adenopathy had been less substantiated. A multi-institutional, prospective, randomized trial showed no difference in overall survival in patients with intermediate thickness melanoma (1–4 mm) who underwent excision alone compared with those patients who underwent excision plus ELND.5 A recent update of this trial demonstrated no significant difference in 10-year overall survival (ELND, 77%; nodal observation, 73%).6 However, an interesting divergence has emerged that possibly supports ELND with longer follow-up evaluation (P value decreasing from .25 reported initially to .12). With the advent of intraoperative lymphatic mapping and sentinel lymph node biopsy (SLNB), the approach to regional nodal evaluation has changed.7 Patients with microscopic disease identified by SLNB now are selected for completion nodal dissection, which also has been called selective lymph node dissection (SLND).

The reported incidence of nodal failure after regional lymphadenectomy for malignant melanoma ranges from 0% to 52%.8–11 Factors associated with nodal failure include the nodal basin dissected,9,11,12 number of involved nodes,8,10 presence of extracapsular nodal disease,10 and patient age.11 However, these prognostic factors were derived from studies with a predominance of palpable (macroscopic) nodal disease rather than microscopic regional disease before the development of SLND. The ability of lymphadenectomy to control regional disease in patients with microscopic nodal disease is not well defined.

Before the introduction of SLNB at the Roswell Park Cancer Institute (RPCI), ELND was applied selectively to patients at high risk for regional metastasis. These included patients with primary melanomas that were ulcerated or of intermediate thickness. In the present report we review our 26-year experience with regional lymphadenectomy for melanoma to evaluate risk factors for nodal failure in patients who initially displayed microscopic lymph node involvement or palpable lymph node metastases. This is one of the largest series to evaluate risk factors for nodal recurrence in a surgical population that did not receive postoperative radiotherapy. Thus, the pure surgical effect of regional lymphadenectomy for malignant melanoma can be assessed. The results of this retrospective study are clinically relevant in the age of SLNB because they can be used to predict nodal failure after resection of microscopic (SLND) or macroscopic (TLND) disease. An additional objective of this study was to evaluate the efficacy of a dissection in patients with a subsequent isolated regional recurrence.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
The RPCI tumor registry was searched for patients treated for cutaneous malignant melanoma from January 1970 to December 1996. Of 2455 patients with cutaneous malignant melanoma, 338 patients (13.8%) were found to have pathologically involved regional lymph nodes. Data collected on review of the medical records of these patients included age at diagnosis, site and depth of primary melanoma, number of nodes involved with disease, presence of matted lymph nodes, presence of extracapsular extension (ECE), use of adjuvant therapy (chemotherapy, immunotherapy, radiotherapy), melanoma recurrence, and date of last follow-up. Information about ulceration or regression of the primary cutaneous melanoma was not uniformly available for interpretation. The RPCI Review Board approved this study.

The surgical technique of lymph node dissection at RPCI has been described previously.13,14 One hundred sixty-four patients (48%) had a diagnosis of nodal metastasis synchronously with the diagnosis of the primary melanoma, and 174 patients (52%) had metachronous presentation of the nodal disease. Seventy-five percent of patients had TLND after they presented with clinically enlarged lymph nodes. The median number of lymph nodes dissected was 18 (range, 1–95). For patients who underwent groin dissections, 42 (35%) patients had a superficial dissection whereas 80 (65%) had a radical dissection. One hundred and forty-eight patients received adjuvant systemic therapy (n = 93), immunotherapy (n = 51), or a combination of both (n = 5) after the initial nodal dissection. Systemic therapy included either Dacarbazine alone or a combination of Vincristine, Actinomycin D, and Carmustine. Immunotherapy included interferon alfa-2b or bacille Calmette-Guérin. After the initial nodal dissection, none of the patients received adjuvant radiation therapy. Follow-up of patients was every 3 months for the first 2 years, then every 6 months for the next 3 years, and then yearly thereafter.

The distribution of demographic, tumor, and treatment characteristics of patients found to have microscopic nodal disease were compared with those treated with TLND for palpable nodes by using the {chi}2 test. Cox proportional hazards model was used to perform univariate and multivariate analysis for factors related to nodal failure.15 The Mann-Whitney U-test was used for univariate analysis of continuous variables. Estimated survival distributions were calculated by the method of Kaplan and Meier.16


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The characteristics of the 338 patients with pathologically involved nodes are detailed in Table 1. The median age of all patients was 50 years and the median follow-up was 29 months (ELND, 42 months; TLND, 24 months). In the entire study population, the most common location of the primary melanoma was the trunk (44%), and the median Breslow depth was 1.9 mm. Overall, axillary lymphadenectomy (47%) and inguinal lymphadenectomy (36%) were the most commonly performed node dissections. Seventy-four percent of patients had fewer than four nodes involved with metastatic disease, and 23% of patients had histologic evidence of ECE of nodal metastases. Although the groups of patients treated with ELND and TLND were similar in age, sex distribution, site of primary tumor, and site of nodal dissection, there were several differences between the two groups. Specifically, patients treated with TLND tended to have larger involved nodes (median size 2.6 cm), greater number of involved (more than four) and matted nodes, and a higher incidence of ECE. In the ELND group, only 10% of patients had more than four involved nodes and only 7% had evidence of ECE.


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  		TABLE 1. Characteristics of the study population
 
The overall incidence of regional nodal recurrence in a dissected basin was 25%. The median time to nodal basin failure was 12 months (range 1–78). Table 2 summarizes the characteristics of the patients who suffered regional recurrence after regional lymphadenectomy for melanoma. There was regional recurrence in 14% of patients treated with ELND (n = 12) and 28% treated with TLND (n = 72; P = .009). In both the ELND and TLND groups, patients with the primary melanoma located in the head and neck region were the most likely to have regional recurrence (27% and 37%, respectively). Similarly, the incidence of nodal recurrence after lymphadenectomy was highest in the cervical basin (ELND 25% vs. TLND 43%). For each nodal basin, the ELND group had a lower incidence of recurrence after lymphadenectomy than the TLND group (Table 2). The number of positive nodes was a significant predictor of local failure, with 25%, 46%, and 63% 10-year actuarial local failure in patients with 1–3, 4–10, and > 10 nodes positive, respectively (P = .008).


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  		TABLE 2. Regional recurrence after elective or therapeutic lymph node dissection Number with regional
 
Multivariate analysis is summarized in Table 3. The factors associated with regional recurrence after lymph node dissection for node-positive melanoma include age, primary site, depth of primary lesion, and ECE. In the ELND group, the site of the primary lesion and ECE predicted risk of nodal failure. For the TLND group, factors associated with risk of nodal recurrence included age, Breslow thickness, Clark level, number of positive nodes, and ECE.


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  		TABLE 3. Multivariate analysis of factors related to regional recurrence after lymphadenectomy for metastatic melanoma
 
The actuarial 5- and 10-year overall survival was 55% and 45% vs. 33% and 26% for ELND and TLND, respectively (P = .0004; Fig. 1). When patients were separated by type of dissection, a significant difference in 10-year disease-specific survival (DSS) was noted between those who underwent ELND (51%) and TLND (30%; P = .0004; Fig. 2). The 10-year DSS of those who suffered a nodal recurrence was 10% vs. 45% for those who did not (P < .0001; Fig. 3). The 10-year DSS was 41% if 1–3 nodes, 22% if 4–10 nodes, and 20% if > 10 nodes were positive (P = .0001; Fig. 4). DSS did not differ significantly between sites of LND. There was no difference in local control or survival in patients with synchronous vs. metachronous lymph node metastases or in patients who did or did not receive systemic therapy. Nodal basin failure was predictive of distant metastases, with 87% of nodal basin failures developing distant disease compared with 54% of patients without nodal recurrence (P < .0001).



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  		FIG. 1. Overall survival based on type of dissection. ELND, elective lymph node dissection; TLND, therapeutic lymph node dissection.

 


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  		FIG. 2. Disease-specific survival based on type of dissection. ELND, elective lymph node dissection; TLND, therapeutic lymph node dissection.

 


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  		FIG. 3. Disease-specific survival based on presence of regional recurrence.

 


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  		FIG. 4. Disease-specific survival based on number of positive lymph nodes.

 
Of the 84 patients who developed regional nodal recurrence, eight patients (10%) had isolated regional nodal recurrence without evidence of distant metastases amenable to consideration of reresection. All eight patients initially had undergone TLND. Measured from the time of the first node dissection, the interval to recurrence ranged from 4 months to 53 months (median 19 months). One patient who underwent a wide local excision of a left leg melanoma with concurrent radical groin dissection recurred in the previous dissection field 32 months later. Because of severe lymphedema, he refused further surgical intervention and subsequently was lost to follow-up. One patient who initially underwent a wide local excision of an ear melanoma and modified right neck dissection for palpable disease recurred within 6 months. He did not undergo a second dissection because of significant comorbidities and subsequently died as a result of a myocardial infarction before initiation of radiotherapy. The remaining six patients underwent a second dissection of their regional lymph node basin. There were one inguinal, two cervical, and three axillary recurrences. After a median follow-up of 64 months (range 11–188 months), the median disease-free interval was 79 months. One patient died of metastatic disease and three patients died of unrelated causes (stroke, myocardial infarction, and arrhythmia) without evidence of disease. Two patients are alive without evidence of melanoma recurrence at 13 years 9 months and 15 years 8 months after their initial lymph node dissection.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Melanoma recurrence in a previously dissected lymph node basin ranges from 9% to 52%.8,10,11,17–21 The risk of recurrence is related to volume of disease in the initially dissected lymph node station and includes palpable adenopathy, multiple involved nodes, and extranodal or extracapsular disease. It has been shown that recurrence is less likely associated with the type of dissection used.20,22,23 Furthermore, it is clear that the biology of the melanoma, and not the surgical procedure, governs outcome.

In the current series, 338 patients were found to have nodal metastases after ELND (n = 85) or TLND (n = 253) for malignant melanoma. Patients who had ELND had a higher frequency of one to three positive nodes (90% vs. 68%) and a lower percentage of ECE (7% vs. 28%). This series represents a unique opportunity to evaluate the risk of nodal recurrence ("pure surgical effect") in a defined set of patients: those with microscopically and macroscopically involved lymph nodes without adjuvant radiotherapy. After a mean follow-up of 28 months, 25% of 338 patients with positive lymph nodes suffered a relapse in the previously dissected lymph node basin. A statistically greater proportion of relapses occurred in those patients in whom palpable disease (28%) vs. microscopic disease (14%) was present.

These results are in keeping with literature that describes relapse rates after therapeutic, elective, and selective lymph node dissection (performed after positive SLNB) as well as prognostic factors associated with the development of nodal recurrence. Belli et al.20 evaluated 93 patients who underwent a radical or modified radical lymph node dissection for palpable nodal disease (TLND). Ten patients (10%) developed nodal recurrence. The type of dissection performed did not influence rates of local relapse, distant metastases, and survival. A similar study carried out by the Sydney Melanoma Unit demonstrated a regional recurrence rate of 28% in 150 patients with positive lymph nodes after a cervical dissection.19 The higher rate of relapse, as compared with the previously study, is likely more accurate and in keeping with our results. There was close patient follow-up and less crossover to other surgeons after relapse, because the majority of patients were entered into a computerized databank and recurrences were documented accurately. As in our study, 10-year survival rates of those patients who recurred (34%) were much worse than those who remained free of disease (67%).

In all nodal basins reviewed, the incidence of regional recurrence was higher in patients who underwent TLND than those found to have microscopic disease after ELND. The highest incidence of regional recurrence (36%) was found in patients with melanomas located in the head and neck region. Multivariate analysis suggests that factors related to regional recurrence may differ for patients with microscopic disease (site of primary tumor, ECE) compared with those with palpable nodal disease (patient age, depth of primary lesion). In univariate and multivariate analysis, the most consistent factor associated with regional recurrence was ECE.

Previous studies have attempted to elucidate the factors associated with nodal failure after regional lymphadenectomy for melanoma. Although an inconsistent variety of factors have been identified as predictors of regional failure, the majority are related to tumor burden in the lymph nodal basin originally dissected. At a minimum of 10 years follow-up, Calabro et al.10 found an overall nodal recurrence rate of 16% in 1001 patients, which was closely related to the number of nodes involved. They also found that extranodal disease was an important factor in predicting recurrence. Miller et al.8 reported an overall recurrence rate of 23% in 78 patients and also found that the number of positive nodes was associated with relapse in the site of a previous node dissection. When one to three nodes was positive, 14% of patients suffered a regional recurrence; when more than four lymph nodes were positive, 53% of patients suffered a relapse. Monsour et al.11 found the highest rate of regional failure in a site of a previous node dissection site: 52% of patients at a follow-up of 24 months. In their series, only patient age was a prognostic indicator for local failure. Thirty-one percent of patients < 50 years old and 60% of patients > 50 years old suffered a recurrence. Warso and DasGupta9 suggested that technical factors may have contributed to the incidence of regional failure. They reported 28 instances of isolated nodal recurrence in 1030 cases of regional node dissection (2.7%). In those cases where the dissection was carried out at their own institution, the rate of relapse was only 0.8%. It is unclear, however, how many of the 1030 patients actually had positive lymph nodes at the initial dissection and, consequently, if there were any differences between the two groups of patients.

The prognosis of patients who suffer a recurrence in a previously dissected basin is poor. Eighty-seven percent of patients in the present study who relapsed regionally were found to have metastatic disease on follow-up. This translated into a 10-year DSS of 10% for those who recurred as compared with 45% for those who did not. Gadd and Coit18 identified an 8% 5-year survival in 74 patients who relapsed in a previously dissected nodal basin.18 Similarly, Calabro et al.10 noted a 5- and 10-year survival of 11% and 5%, respectively, in a comparative group of patients.

Few patients present with an isolated nodal recurrence after a lymph node dissection for positive disease. In the present series, only 8 of 84 patients (10%) developed isolated nodal recurrence without evidence of distant disease amenable to reresection. However, once metastatic disease has been ruled out, a second dissection should be performed because it may offer a survival benefit in carefully selected situations. Long-term survival was demonstrated in two of six patients who underwent a second dissection of the regional lymph node basin. A similar series of second dissection for nodal basin recurrence was reported by Warso et al.9 The median survival after dissection was 14 months among 28 patients who presented with recurrence in their lymph nodes as the only site of recurrence and who underwent a second operation. At follow-up, however, four patients were alive without disease with survival that ranged from 4 years 1 month to 14 years 1 month, and two were alive with disease from 1 year 3 months to 5 years 5 months postoperatively. Although three patients died of unrelated causes in our series, a total of five patients were deemed free of disease after the second dissection. When evaluated together, their median disease-free interval was 79 months (range, 7–149 months). A local surgical approach also is warranted in patients with combined systemic and bulky regional disease to prevent difficult wound management problems, patient discomfort, or bleeding.

Despite the significant incidence of regional failure after node dissection for melanoma, few studies have attempted to address means to improve regional control. Traditional approaches have included redissection of the basin especially if there are technical concerns with regard to the initial procedure. Radiotherapy has been shown in single institution trials to achieve nodal basin control in 87% to 95% of patients.12,24–26 Because of the dismal prognosis associated with nodal basin failure, attempts at preventing initial failure should be prioritized. Based on risk factors for nodal recurrence described here, one can stratify patients into low and high probability for recurrence and can consider adjuvant radiotherapy for the latter. The National Comprehensive Cancer Network now recommends the use of radiotherapy in high-risk patients: those with multiple involved nodes or extranodal disease, especially in the head and neck region.27 The addition of radiotherapy, however, has failed to translate into a survival advantage.

In summary, our results are consistent with those found in the literature but also suggest that factors associated with local control may differ for ELND and TLND. The fact that patients with ELND have a higher frequency of one to three positive nodes and a lower percentage of ECE suggests that regional nodal disease should be addressed when it is microscopic. The similarity of those patients who have undergone an ELND to those patients with a positive sentinel lymph node who undergo completion nodal dissection also makes a stronger argument for SLN procedures.28 Nodal recurrence frequently heralds systemic disease and as a result is associated with a dismal prognosis. Thus, every attempt should be made to control stage III disease for malignant melanoma when it is microscopic. That means lymphatic mapping and SLNB for high-risk patients and adjuvant radiotherapy for patients with four or more positive nodes or ECE, because the consequences of nodal recurrence are severe. The findings in the present study may have implications for adjuvant treatment decisions, stratification of clinical trials, and progressive approaches to the results of sentinel node biopsy.


   Footnotes
 
Presented at the Society of Surgical Oncology Cancer Symposium, New Orleans, Louisiana, March 16–19, 2000.

Received for publication March 16, 2000. Accepted for publication September 21, 2000.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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