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Role of Sentinel Lymphadenectomy in Thin Invasive Cutaneous Melanomas

Richard J. Bleicher, Richard Essner, Leland J. Foshag, Leslie A. Wanek, Donald L. Morton

From the John Wayne Cancer Institute at Saint John’s Health Center, Santa Monica, CA.

Address reprint requests to Richard Essner, MD, John Wayne Cancer Institute, 2200 Santa Monica Blvd, Santa Monica, CA; email: essnerr{at}jwci.org.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Purpose: Regional lymph node status is the strongest prognostic determinant in early-stage melanoma. Lymphatic mapping and sentinel lymphadenectomy (LM/SL) is standard to stage regional nodes because it is accurate and minimally morbid, yet its role for thin ( 1.5 mm) primary melanomas is unknown.

Patients and Methods: Our melanoma database of more than 10,000 patients was reviewed for patients with melanomas 1.50 mm thick who underwent LM/SL. All had lymphoscintigrams and LM/SL via dye alone or with radiopharmaceutical. Patients with tumor-positive sentinel nodes (SNs) underwent completion dissections.

Results: Five hundred twelve patients underwent LM/SL. Most were men (57%), and median age was 49 years. Most primary melanomas were on the torso (44%). Twenty-five patients (4.9%) had tumor-positive SNs. The thinnest lesion with a nodal metastasis was 0.35 mm. The SN-negative and SN-positive cohorts were equivalent by sex, but SN+ patients tended to be younger (P = .053), with significantly more SN metastases in those younger than 44 years (P = .005). No consistent pathology among SN-positive primary melanomas was found. Among those with 1.01- to 1.05-mm primaries, 7.1% were SN-positive. Among 272 patients with lesions 1.00 mm, 2.9% had positive SNs and 1.7% with lesions 0.75 mm had SN metastases. All 13 deaths were in SN-negative patients. Median follow-up durations in SN-positive and SN-negative patients were 25 and 45 months, respectively.

Conclusion: The high nodal positivity rate associated with primary melanomas 1.01 to 1.50 mm thick suggests that LM/SL is indicated in this group. Younger age may be correlated with nodal metastases in patients with lesions 1.00 mm. Lesions 0.75 mm have minimal metastatic potential, and therefore LM/SL is rarely indicated.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
EVALUATION AND staging of melanoma has changed dramatically with the introduction of intraoperative lymphatic mapping and sentinel lymphadenectomy (LM/SL), first presented by Morton et al¹ at the Society of Surgical Oncology in 1990. Since that time, LM/SL has been validated to accurately reflect the nodal status of the regional basins draining primary cutaneous melanomas. With an identification rate as high as 99% in experienced hands,² LM/SL is becoming the standard for staging the regional lymph nodes.

The indications for LM/SL, however, continue to evolve. There is no current consensus within the literature as to which lesion characteristics justify performance of LM/SL, and institutions offer LM/SL to varying subsets of patients^3–5 with thin primary melanomas. These patients may have lesions 0.75, 1.0, or even 1.5 mm.^3,6,7 We therefore examined the sentinel node (SN) status of all patients at our institution who underwent LM/SL for American Joint Committee on Cancer stages I and II melanomas that were 1.5 mm in thickness and substratified the patients into these thickness categories to further clarify the application of LM/SL in these lesions.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Selection Criteria and Study Variables
All John Wayne Cancer Institute (Santa Monica, CA) patients with melanoma evaluated from April 1972 to the present have been prospectively followed and their data entered into a computerized database that currently contains more than 10,000 patient entries. This database was queried for patients with primary cutaneous melanomas 1.50 mm in thickness who underwent successful LM/SL at our institution within 90 days of wide local excision (or initial biopsy). Patients with clinical lymphadenopathy or question of distant metastases were excluded. In addition, any individuals demonstrating multiple concurrent primary melanomas (defined as two primary tumors within 90 days) were eliminated to avoid possible errors in correlation between a primary melanoma and its lymphatic spread. Only the first melanoma and sentinel node data in those patients with more than one successive primary melanoma were included in the analysis. Patients with a history of melanoma treated elsewhere before presentation to the John Wayne Cancer Institute for a second primary melanoma were therefore also excluded. Patients who had previous excisions more than 2.0 cm and therefore who were not candidates for LM/SL were also excluded.⁸

The remaining patients’ records were reviewed for Clark level, sentinel node status, patient age, sex, primary tumor location, recurrence, and survival. Charts were then examined in detail on those patients whose final pathology demonstrated disease within the sentinel node by hematoxylin and eosin or immunohistochemical staining. Initial biopsy type, initial biopsy margin status, and method of histologic identification of nodal metastatic disease were reviewed. The histologic characteristics found in the SN-positive lesions (lymphocytic infiltrate, ulceration prominent vertical component, and regression) were noted with their corresponding data.

Lymphatic Mapping
Our technique of LM/SL has been previously described elsewhere.² Currently, all patients undergo cutaneous lymphoscintigraphy with one of three radiopharmaceuticals either several days before or on the day of the operative procedure. The skin site identified by lymphoscintigraphy is 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) is injected intradermally at the primary melanoma site. The skin is gently massaged to enhance the drainage of isosulfan blue into the regional lymphatics. An incision is made over the skin site marked by the nuclear medicine physician. The afferent lymphatics are examined for blue-staining and followed from the edge of the wound to the first blue-stained node (SN). A handheld gamma probe is used to determine the radioactive counts over this node, over adjacent nonblue nodes, and over an irrelevant background site. Probe-identified SNs are defined by a radioactive count at least two-fold higher than background.^9,10 All dye-identified and/or probe-identified SNs are excised and examined for the presence of metastases. If tumor is identified, then complete lymphadenectomy is performed.

Histopathologic Examination of the Sentinel Node
Sentinel nodes were initially evaluated by frozen-section analysis during development of the SL technique¹¹ but are now reviewed only by permanent sections to minimize loss of diagnostic material during examination. After fixation in paraffin, each SN is dissected through its longest axis. Ten serial sections are removed and embedded in paraffin for sectioning and examination with both hematoxylin and eosin and immunohistochemical staining with antibodies for S-100 and the melanoma-specific protein HMB-45.

Statistical Analysis
Statistical correlation and analysis was performed using SAS software (SAS Institute, Cary, NC). A two-tailed P value of less than .05 was considered statistically significant to reject the null hypothesis. Patient age and thickness of the primary melanoma were analyzed as continuous factors; other factors were analyzed as categorical. Survival times were calculated from the time of the SL procedure until last follow-up date or date of death. Proportions were compared using the standard ² statistic, and continuous variables were compared by standard test methods. Estimated survival rates were calculated by the Kaplan-Meier method. The conditional probability of recurrence was defined as the percentage of patients who recurred among those who were still at risk during a given year after SL.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
During the study period, there were 1,661 patients with lesions 0.75 mm, 774 patients with lesions between 0.76 and 1.00 mm, and 993 patients with lesions between 1.01 and 1.50 mm seen at the John Wayne Cancer Institute. Those patients who underwent SL and who fulfilled the remainder of our criteria constituted 7.1%, 19.9%, and 24.2% of these individuals, respectively.

This resulted in 512 patients who met our study criteria and presented to our institute for treatment from June 1985 to December 2000. Of the 512 patients, 118 patients had primary melanomas that were 0.75 mm (group I), 154 patients had primary melanomas that were 0.76 to 1.00 mm (group II), and 240 patients had primary melanomas that were 1.01 to 1.50 mm (group III). Corresponding mean depths were 0.58 ± 0.13, 0.89 ± 0.07, and 1.26 ± 0.13 mm for the three groups, respectively. Twenty-five patients had tumor-positive SNs after LM/SL (1.7% of group I, 3.9% of group II, and 7.1% of group III).

Age data overall and by group are listed in Tables 1 and 2, respectively. Analysis of SN-positive and SN-negative patients demonstrated a significant difference in age only between groups I and III (P = .0074). SN-positive patients tended to be younger than SN-negative patients for the entire study group (P = .053) and within group III alone (P = .054), which was the largest thickness cohort. No age trend was found within the SN-positive patients, but the ages of SN-negative patients increased with lesion thickness (analysis of variance, P = .029). The threshold below which the presence of an SN metastasis was most significant was 44 years of age (< 44 years, 8.3%; 44 years, 2.8%; P = .005).

View this table: [in this window] [in a new window]   Table 1. Clinical Features of Patients With Primary Tumors 1.50 mm Undergoing Lymphatic Mapping and Sentinel Lymphadenectomy

Review of the initial biopsies of the SN-positive patients was performed to determine whether the initial biopsy underestimated the true thickness of the primary melanomas. Of the SN-positive patients, 14 had complete excisional biopsies, 12 were diagnosed by incomplete excisional biopsy, and in one patient, the margin status was not clear. The thinnest SN-positive lesions completely and incompletely excised on initial biopsy were 0.8 and 0.35 mm thick, respectively. Among these 25 SN-positive lesions, only one lesion diagnosed by incomplete biopsy had a thickness measurement that increased on review of the wide local-excision specimen, from a 0.9-mm Clark level III to a 1.5-mm Clark level IV. Nineteen of the initial biopsies were not classified as excisional or tangential, but there was no difference in thickness between the two biopsy methods when specified. The anatomic distribution of the primary lesions is listed in Table 1.

In the 25 patients with tumor-positive nodes, 1.24 lymph nodes were found to contain metastases per patient, compared with 2.20 SNs excised in these patients. As indicated in Table 3, only a minority of cases required immunohistochemical staining for identification of metastatic disease not first seen on hematoxylin and eosin stains. The nodal metastatic deposits were noted by either their size or cell number. Metastatic deposits were noted to be between 0.1 and 10 mm in 13 patients and were described by cell number in eight patients, ranging from four- to 12-cell clusters, with only one patient notable for a single atypical cell. Samples from four patients were not defined.

There was no statistical difference between the groups in the time from wide excision of the primary lesion to SL. Recurrence and disease-free survival data for all subsets analyzed are presented in Table 4 and Fig 1, and the conditional probability of recurrence for node-negative patients was 0.90% at year 1 and maximal at year 3 (1.32%), decreasing thereafter. The death rate in each group was too low to calculate overall and median survival (Table 5). Analysis of lesions by location (axial v extremity) also demonstrated no correlation with disease-free or overall survival (P = .43 and .67, respectively).

View larger version (11K): [in this window] [in a new window]   Fig 1. Disease-free survival in sentinel node–positive (SN+) and sentinel node–negative (SN-) patients (P = .0031; log-rank test).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Although it is well known that the incidence of lymph node metastases increases with increasing thickness of the primary melanoma,¹² indications for elective lymphadenectomy have been controversial for some time. With the more frequent application of LM/SL for melanoma and the increasing incidence of thinner lesions, practice guidelines for application of LM/SL to such lesions are required.

Our study confirms that even primary melanomas 1.5 mm tend to metastasize more readily to the SN as thickness increases, and that melanomas 0.75 mm can demonstrate nodal metastases contrary to prior reports.^5,13–16 Although thinner lesions statistically pose less risk of metastatic nodal involvement, any depth of invasion carries the possibility of an SN metastasis. This is best demonstrated by one patient in this study whose 0.35-mm Clark level II lesion with no evidence of regression or ulceration metastasized to an SN. Such patients underscore the need to identify indications for LM/SL in thinner melanomas.

We found a 1.7% incidence of SN metastasis from lesions thinner than 0.76 mm. Although smaller studies examining SN status in lesions of this caliber document no lymph node metastases,^5,13–16 in 1980 (before the introduction of SL), Woods et al¹⁷ noted a 3% metastasis rate in 400 lesions 0.75 mm over a 10-year period. With such a low incidence of nodal positivity, it would be difficult to justify routine examination of SNs in anyone but those at highest risk in this population. Additional efforts to define the characteristics of such individuals are necessary.

In contrast, melanomas between 1.01 and 1.50 mm thick had a substantial 7.1% nodal positivity rate, indicating that the decision to perform LM/SL in melanomas 1.01 to 1.50 mm may be justifiable solely on the basis of lesion thickness. It is those patients with lesions of 0.76 to 1.00 mm and an SN metastasis rate of 3.9% who have the greatest need for guidelines on the basis of this intermediate risk for metastasis.

We have confirmed that Breslow measurement and Clark level generally are correlated even within thin lesions. Although the Clark level seemed to increase with thickness, no statistical correlation existed between Clark level and nodal positivity. We have previously reported that patients with lesions less than 0.75 mm have a significantly shorter overall survival as Clark level increases.¹⁸ Patients with melanomas 0.75 to 1.49 mm mimicked this trend, but not significantly.¹⁸ In contrast, Owen et al¹⁹ substratified 4,560 melanomas in a manner identical to this investigation and found no difference in survival between Clark level III and IV lesions. Even when Clark level II and III lesions were combined in this study and compared with Clark IV lesions (such as in historical staging), no difference in SN metastases existed. These conflicting observations suggest that although deeper Clark level may indicate higher risk, they do not support mandating SL in all Clark level IV lesions regardless of thickness. We therefore recommend that Clark level remain one factor to be considered in currently equivocal situations, such as in patients with lesions 1.00 mm.

To our knowledge, age has not been recommended as a screening criterion for SL in thin lesions. It has, however, been known to be prognostic. A mathematical model established by Joseph et al²⁰ predicted that risk for SN metastases increases in younger patients. In our study, SN-positive patients tended to be younger than SN-negative patients, both overall in patients with lesions 1.50 mm and in group III, the largest subgroup. Had our patient population been larger, it is likely that this trend would have been maintained in groups I and II.

In response to this finding, we attempted to define a specific age for clinical purposes below which risk may be increased. Across all patients with lesions 1.5 mm, those younger than 44 years had the most significant increase in their incidence of SN metastases when compared with those patients 44 years of age and older (P = .005). This significance was maintained but was not as prominent around ages 40 (P = .029) through 45 years (P = .014). This suggests that age is a prognostic factor for SN status, especially for patients in their early 40s or younger. We would therefore consider such patients with lesions 1.00 mm more strongly for SL but also believe that this observation requires confirmation in a larger data set.

Studies have also attempted to correlate factors such as sex, primary location, regression, ulceration, mitotic rate, lymphovascular invasion, lesion size, extent of vascularization, nuclear pleomorphism, and DNA content,^13,21–23 all with variable success. Slingluff et al²⁴ found male patients with axial primary melanomas 0.75 mm with regression or Clark level IV invasion to be at greatest risk for distant metastatic disease. Our data did not find sex, axial location, or regression to be predictive of sentinel nodal status. In fact, review of the pathology of the primary lesions revealed no findings that were predictive of nodal positivity. We therefore cannot recommend these factors as stand-alone indications for performance of LM/SL in thin lesions at this time.

Factors established as prognostic in intermediate-thickness lesions include age, sex, location, ulceration, and regression. Although some risk factors already established for thicker lesions were not significant in this cohort, disregarding their presence completely would be unwise, especially in lesions between 0.76 and 1.00 mm. The incidence of SN positivity in primary melanomas 0.75 mm is even less frequent, but such factors should continue to be considered, because confirmation of their importance would likely necessitate an extremely large cohort.

Despite these findings, indications for LM/SL are only important if the SL accurately assesses metastatic disease. We found that none of our patients with SN metastases had additional disease on completion lymphadenectomy. In addition, there were no nodal recurrences in SN-negative patients (who did not undergo completion lymphadenectomies). These combined factors corroborate the accuracy of the SLs even in thin lesions. Findings also indicate that although metastatic potential exists, it may be comparatively limited in thinner lesions. This suggests that LM/SL (especially in lesions 1.00 mm) may not require completion dissection, and additional study is warranted.

Accurate assessment of nodal status in thin melanomas is assumed to be important, but it too remains meaningless unless it reflects outcome as in thicker lesions. We found that the conditional probability of recurrence was maximal in year 3. The sizes of these micrometastases were as small as a single cell in one patient; nonetheless, the percentage of recurrences was higher in patients with SN metastases (12.0%) than in those with negative SNs (3.7%), despite longer follow-up in the latter group. In addition, despite the overall population’s low risk, we have confirmed a statistically significant difference in disease-free survival dependent on the nodal status of the patient (Fig 1). Finally, there was such a low mortality rate in each subgroup that it precluded calculation of accurate survival and 5-year point estimates. The only deaths were observed in SN-negative patients, probably because of the shorter follow-up period in the SN-positive group.

During the study period, not all patients with lesions 1.50 mm underwent LM/SL. This was due to the evolution of LM/SL indications after we introduced and perfected the technique. In addition, because of the retrospective nature of the study and the multifactorial nature of the decisions, we have been unable to quantify trends for any particular decision factor in choosing to perform LM/SL since 1985. We should note, however, that patients who requested the procedure (especially early in our experience), who had Clark level IV lesions, and whose initial biopsies were indicated for ulceration or regression were considered more strongly for LM/SL. These factors illuminate the possibility of selection bias inherent to a retrospective investigation and mandate continued study to confirm our observations.

Despite our evidence that SN metastases occur in lesions less than 0.76 mm, we cannot routinely recommended LM/SL in such patients because of morbidity and cost. Even patients with lesions 0.76 to 1.00 mm, whose incidence of positive SNs is twice that of those with lesions less than 0.76 mm, require appropriate selection. Wrightson et al²⁵ reported a 6% SL complication rate in 1,202 patients, and although their LM/SL cohort overlapped with their completion lymphadenectomy cohort, making the exact LM/SL complication unclear, potential morbidity must be considered.

Cost data associated with LM/SL is also sparse, although we found that our LM/SL added approximately $915 to the surgical and operating room cost and $1,811 to the overall cost of a wide local excision (including operative and postanesthesia recovery). These costs did not include missed or limited employment from convalescence and medical follow-up and exclude any psychologic components to the family and patient. Without LM/SL, many wide local excisions not necessitating skin grafts can be performed in a clinic or minor operating room setting, which further decreases operative expenses. The cost of LM/SL must therefore be balanced against its benefit, especially in patients with little risk of nodal metastases.

In this study, we also evaluated the primary biopsy margin status in a sample of patients to indicate the accuracy of the initial thickness measurement. The SN-positive group was used as the sample because the true depth of these lesions is most critical and subject to speculation. Because most of the biopsies were performed before referral and because 39% were not classified as excisional or tangential (shave biopsies), we reviewed the widely available margin status of these biopsies. The thinnest lesion with negative margins was 0.8 mm, but only one lesion’s thickness was upstaged on wide local excision. In light of this finding, and the reality that positive margins are commonly seen before referral for definitive treatment, initial biopsy thickness measurements must be accepted de facto. An incomplete biopsy may add error to thickness assessment on subsequent wide excision because of wound healing at that site.^26,27 We therefore recommend that even though lesion thicknesses must be taken at face value, the inherent error owing to an initial biopsy with positive margins should decrease the threshold for performance of LM/SL.

Melanomas thinner than 0.76 mm rarely metastasize to the SN, and we therefore cannot routinely recommend LM/SL in this group of patients. Those with melanomas whose thicknesses measure between 0.76 and 1.00 mm, however, should be evaluated for LM/SL on a case-by-case basis. Individuals in these groups should be more strongly considered for this procedure if they are in their early 40s and younger, if their melanomas are Clark level IV lesions, or if their initial biopsies demonstrate positive margins. The influence of established intermediate-thickness risk factors on lesions 1.00 mm must currently be left to the discretion of the surgeon. Additional data accrual may eventually pinpoint exactly which patients with lesions 1.00 mm should undergo LM/SL. Currently, however, we do recommend that all patients with melanomas between 1.01 and 1.50 mm undergo LM/SL solely based on thickness as a result of their high incidence of SN positivity.

	NOTES

 
Supported by grant no. CA29605 from the National Cancer Institute and Saban Family Foundation.

Presented at the Thirty-Eighth Annual Meeting of the American Society of Clinical Oncology, May 18–21, 2002, Orlando, FL.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted June 19, 2002; accepted December 23, 2002.

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