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Originally published as Ann Surg Oncol Early Release 10.1245/ASO.2004.10.002 on September 20, 2004

Annals of Surgical Oncology 11:900-906 (2004)
© 2004 Society of Surgical Oncology
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Article

Indications for Lymphatic Mapping and Sentinel Lymphadenectomy in Patients with Thin Melanoma (Breslow Thickness ≤1.0 mm)

Karyn B. Stitzenberg, MD, Pamela A. Groben, MD, Stacey L. Stern, MS, Nancy E. Thomas, MD, Thomas A. Hensing, MD, Leah B. Sansbury, MSPH and David W. Ollila, MD

From the Department of Surgery (KBS, DWO), Department of Pathology (PAG), Department of Dermatology (NET), and Division of Surgical Oncology (DWO), School of Medicine; the Cecil G. Sheps Center for Health Services Research (KBS); and the Department of Epidemiology, School of Public Health (LBS), University of North Carolina, Chapel Hill, North Carolina; CancerVax Corporation (SLS), Carlsbad, California; and Department of Medicine (TAH), Evanston Northwestern Healthcare, Evanston, Illinois

ABSTRACT

Background: Patients with thin (Breslow thickness ≤1.0 mm) melanoma have a good prognosis (5-year survival >90%). Consequently, the added benefit of lymphatic mapping and sentinel lymphadenectomy (LM/SL) in these patients is controversial. We hypothesize that LM/SL with a focused examination of the sentinel node (SN) will detect a significant number of SN metastases in patients with thin melanoma and that certain clinical or histopathologic factors may serve as predictors of SN tumor involvement.

Methods: Over 6 years, 349 patients with melanoma underwent LM/SL and were prospectively entered into an institutional review board (IRB)-approved database. LM/SL was performed with a combined radiotracer and blue dye technique. SNs were serially sectioned, and each section was examined by a dermatopathologist at multiple levels with hematoxylin and eosin as well as immunohistochemical stains.

Results: One hundred forty-six patients (42%) had a melanoma with Breslow thickness ≤1.0 mm; six (4%) of these 146 patients had a tumor-involved SN. On multivariate analysis, none of the clinical or histopathologic factors examined were significantly associated with SN tumor involvement in patients with thin melanoma. Completion lymphadenectomy was performed on all patients with a tumor-involved SN. None of the patients had non-SN tumor involvement.

Conclusions: The incidence of SN tumor involvement in patients with thin melanoma is considerable. Although we were unable to identify predictors of SN tumor involvement in patients with thin melanoma, efforts to identify predictors of SN tumor involvement should continue. Until better predictors are identified, we continue to advocate offering LM/SL to patients with thin melanomas who demonstrate clinical or histopathologic characteristics that have historically been associated with an increased risk of recurrence and mortality.

Key Words: Incidence • Lymphatic mapping • Sentinel node • Staging • Thin melanoma

Over the past 3 decades the incidence of melanoma has been increasing.2–5 An estimated 54,200 people in the United States had a new melanoma diagnosed in 2003. On the basis of data from the Surveillance, Epidemiology, and End Results program, between 1988 and 1997 the estimated annual percent increase in melanoma incidence was 2.5% for women and 3.4% for men.4 Over the same period, the incidence in thin melanoma (Breslow thickness ≤1.0 mm) increased out of proportion to the incidence of all cutaneous melanoma.4 Currently, 50% to 75% of the patients with diagnosed cutaneous melanoma in the United States have a thin melanoma.6–8 For these patients with thin melanoma, there is roughly a 10% to 15% risk of recurrence and death at 10 years.1,9 Although multiple groups have attempted to identify risk factors for recurrence, there currently is no effective means of determining which patients with thin melanoma will relapse and/or die as a result of metastatic disease.10–16

Since the introduction of lymphatic mapping and sentinel lymphadenectomy (LM/SL) for melanoma by Morton et al. in 1990, LM/SL has become the preferred method for determining the histopathologic status of the regional lymph nodes for patients with intermediate-thickness (>1.0 mm, ≤4.0 mm) melanoma. LM/SL can accurately identify the first draining lymph node(s), the sentinel node (SN), in patients with cutaneous melanoma. In experienced hands, the tumor status of the SN is highly predictive of the tumor status of the entire nodal basin.17–22

The added benefit of LM/SL in patients with thin melanoma remains controversial.9,10,23–27 Overall, patients with thin melanoma who undergo appropriate wide local excision of the primary tumor have a good prognosis (10-year survival, roughly 85% to 90%).1,9 Still, there is a subgroup of patients with thin melanoma who are at increased risk of recurrence and death.16 The Breslow thickness of the primary tumor and the nodal status of the patient are the strongest predictors of long-term survival for all patients with melanoma.10 Since data from the elective lymph node dissection (ELND) era revealed tumor-involved lymph nodes in only 1% to 3% of patients with thin melanoma,16,28 LM/SL has not been routinely recommended to these patients.

However, the incidence of nodal tumor involvement in patients with thin melanoma may be higher than previously recognized. Specimens from the ELND era, in general, underwent examination at only one hematoxylin and eosin (H&E)–stained level. This type of pathological evaluation has been shown to miss as many as one-third of nodal metastases.29 LM/SL permits a more thorough examination of a smaller specimen, reducing the risk of missed metastases. Since no group has performed LM/SL on all patients with thin melanoma, the true incidence of nodal tumor involvement in these patients is unknown.30 As a result, the use of LM/SL in this cohort remains controversial.23–27,30–36

With the increasing absolute number of patients with thin melanoma and the 5% to 15% mortality rate at 10 years for these patients, the role of LM/SL in patients with thin melanoma needs to be re-evaluated. The aims of this study were to quantify the risk of nodal tumor involvement for patients with thin melanoma and to begin to identify patients with thin melanomas who may be at increased risk for nodal metastases. We hypothesize that LM/SL with a systematic, focused examination of the sentinel node (SN) will detect a substantial number of SN metastases in patients with thin melanoma and that certain clinical or histopathologic characteristics may serve as predictors of SN tumor involvement in patients with thin melanoma.

METHODS

Patient Selection
Between January 1998 and January 2004, all patients with a primary melanoma of Breslow thickness ≥0.75 mm and no evidence of nodal or distant metastases on clinical examination were offered LM/SL at our institution. Patients with primary tumors of Breslow thickness <0.75 mm were offered LM/SL only if one of the following criteria was met: Clark’s level IV or V, ulceration, regression, or patient demand. All patients who underwent LM/SL were prospectively entered into a database that has been approved by the University of North Carolina School of Medicine Institutional Review Board, and informed consent was obtained from all participants.

Surgical Methods
LM/SL was performed with use of a combined 99mtechnetium-labeled sulfur colloid and isosulfan blue dye technique. Techniques for LM/SL combining both blue dye and 99mtechnetium-labeled sulfur colloid (Nicomed; Amersham Canada, Ltd., Oakville, Ontario, Canada) have been described previously.37–41 In the nuclear medicine department, 99mtechnetium-labeled sulfur colloid was injected intradermally at the site of the primary lesion or previous biopsy on the morning of surgery. Preoperative lymphoscintigraphy was performed in all cases to identify and document the involved nodal basins.

In the operating room, 0.5 to 1.5 mL of isosulfan blue dye (Lymphazurin, Hirsch Industries, Inc., Richmond, VA) was injected intradermally around the patient’s primary melanoma or previous biopsy site. The area was then compressed for 3 to 10 minutes. Prior to skin incision, the area within the nodal basin with the greatest number of counts per second was located with a commercially available hand-held gamma detection probe. An incision was made in this area. Careful dissection of the underlying tissue was performed until a blue-stained lymphatic channel was located. If the blue-stained lymphatics were difficult to find or follow, the hand-held probe was used to direct the dissection. Once identified, the blue lymphatic channel was tracked proximally and distally until a blue node was located. This node was removed and labeled as the SN. The ex vivo SN activity and the residual background activity in the nodal basin were then documented. If the ratio of the ex vivo SN counts per second to the background counts per second remained >10:1 after removal of the SN, the dissection was continued to identify and remove all additional SNs. If radiotracer activity had been identified in multiple nodal basins on preoperative lymphoscintigraphy, the above procedure was repeated for each involved nodal basin.

Histopathologic Examination of Sentinel and Nonsentinel Nodes
All melanoma cases at our institution are handled by a board-certified dermatopathologist. For patients whose diagnostic biopsies are performed elsewhere, pathologic specimens are reviewed by one of the dermatopathologists at our institution to confirm the diagnosis and the histopathologic characteristics of the lesion. For the purposes of this study, the primary tumors and SN specimens of all cases of thin melanoma with a positive SN were reviewed again by a single dermatopathologist (P.A.G.).

As previously described in detail, all SNs at our institution are step-sectioned.42 The SN is first bivalved along the shortest axis. Each half is then rotated so that the cut surface faces up. The halves are placed adjacent to each other, and the node is subsequently sectioned, parallel to the cut surface, into approximately 1-mm slices. Alternating slices are sent to surgical pathology and to the University of North Carolina Lineberger Comprehensive Cancer Center Tissue Procurement and Analysis Core Facility for current and future studies.

The tissue submitted to surgical pathology is fixed in formalin, processed overnight, and embedded in paraffin. Initial evaluation of each SN entails examination of a single H&E-stained slide from each 1-mm SN slice. If a metastasis is discovered during the initial H&E examination, no further sections are obtained from the SN. For SN specimens that are tumor-free on this initial H&E examination, additional levels are obtained and stained with S100 and MART-1 immunohistochemical stains with two intervening H&E sections.

Initially at our institution, SNs that were tumor-free by H&E examination were further examined with S100 immunohistochemical staining. However, after Shidham et al. published their report on the improved diagnostic accuracy for detecting micrometastatic disease with melanoma antigen recognized by T cells (MART-1), we added MART-1 to our immunohistochemical panel.43 We now rely on the combination of S100 and MART-1 to detect micrometastatic disease in the SN.

Statistical Methods
The associations between SN tumor status and the following clinical and histopathologic factors were evaluated: age, gender, race, primary site, Clark’s level, Breslow thickness, ulceration, and regression. Continuous variables were analyzed with a simple logistic regression model. Dichotomous and categorical variables were analyzed with a Pearson {chi}2 test. Analysis was repeated with Fisher’s exact test because observations were few. Multivariate logistic regression analysis, including all the variables, was then performed.

RESULTS

Over the 6 years of data collection, 349 patients underwent LM/SL. Patient demographics and primary tumor characteristics are summarized in Table 1. One hundred forty-six patients (42%) had a thin melanoma (Breslow thickness ≤1.0 mm). While the gender, race, and primary site of the patients with thin melanoma were comparable to those of the group as a whole, patients with thin melanoma tended to have less advanced Clark’s levels (74% had Clark’s I–III) and were less likely to have ulceration of the primary tumor.


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  		TABLE 1. Demographics of all patients who underwent lymphatic mapping and sentinel lymphadenectomy compared to patients with thin melanoma who underwent lymphatic mapping and sentinel lymphadenectomy

 

Six (4%) of the 146 patients with thin melanoma who underwent LM/SL had a tumor-involved SN. In contrast, 36 (18%) with a melanoma of Breslow thickness >1.0 mm had a tumor-involved SN. The Breslow thickness for the six patients with thin melanomas who had a tumor-involved SN ranged from 0.4 to 0.9 mm (mean, 0.69 mm) Table 2. Two patients were male and four were female. The Clark’s level for these six patients ranged from II to IV. None of their primary lesions were ulcerated or showed evidence of regression. Four of the six cases had vertical growth phase evident on histopathologic examination. On univariate and multivariate analysis, none of the factors examined were significantly associated with SN tumor involvement in the patients with thin melanoma. Table 3.


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  		TABLE 2. Details of the patients with a primary tumor ≤1.0 mm thick who had a tumor-involved SN

 

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  		TABLE 3. Associations between SN tumor involvement and multiple clinical and histopathologic factors in patients with thin melanoma

 

Completion lymph node dissection was performed on all patients with a tumor-involved SN. None of the patients with a thin melanoma had non-SN tumor involvement. Systemic adjuvant interferon or an adjuvant immunotherapy trial was recommended to all patients with an SN metastasis.

DISCUSSION

Many investigators have attempted to identify clinical and histopathologic characteristics that are predictive of recurrence and/or mortality in patients with early stage melanoma. Associations between risk of recurrence and all of the following factors have been described: Breslow thickness,10,16,44,45 gender (male16,44,45 and female14), axial lesions,15,16,44 regression,16 ulceration,10,13,15,44,45 increased mitotic activity,14,15 increased Clark’s level,10,11,14,15 and age.44 Unfortunately, these studies have often had conflicting results. The only factors that are consistently associated with increased risk of recurrence and mortality are Breslow thickness, ulceration, and nodal status. As a result, these are the basis for the current American Joint Committee on Cancer (AJCC) staging system.1

For patients with thin melanoma, there is also a consistent association between increased Clark’s level and increased risk of recurrence; this has led to the inclusion of Clark’s level in the AJCC staging system for thin melanoma.10 Some groups have suggested that LM/SL should be considered in all patients with thin melanomas with Clark’s level IV or V primary lesions.11,24,27,33,34,46 In contrast, because of the historically low incidence of nodal metastases in patients with thin melanoma (1%–3%), other groups have concluded that increased Clark’s level alone is not sufficient to justify LM/SL in these patients.24,30,35,36

LM/SL is a highly accurate method for histologic staging of the regional nodal basin that is associated with minimal procedure-related morbidity.35,47–49 Although long-term survival results from prospective randomized controlled trials of LM/SL for melanoma are not yet available, the retrospective data suggest that patients with micrometastatic stage III melanoma fare better than those with macrometastatic disease. In single-institution studies, comparison with simple observation of the regional nodal basin for clinically palpable nodal disease has demonstrated that patients whose nodal metastases are detected earlier as micrometastatic disease have better overall survival than patients in whom nodal disease is detected later as macrometastatic disease or palpable adenopathy.11,50–52 Consequently, if a group of patients with thin melanomas who are at substantial risk of harboring micrometastatic disease in the SN can be identified, they may benefit from LM/SL.

In our current study, 4% of patients with thin melanomas who underwent LM/SL had SN tumor involvement. These patients subsequently underwent completion lymph node dissection and were offered adjuvant therapy. If LM/SL had not been performed, these patients would have been considered node-negative, and no additional therapy would have been offered. Although long-term prospective data are not yet available, we believe this aggressive approach to identifying micrometastatic nodal disease will result in improved overall survival for a considerable number of patients with thin melanoma.

Recognizing that only some patients with thin melanoma are at an increased risk of nodal metastasis, investigators have sought to identify predictors of SN tumor involvement that might identify "high risk" patients with thin melanoma. Breslow thickness,53 regression,31 ulceration,32 advanced Clark’s level,34 increased mitotic activity,32,54 and vertical growth phase23,32 have all been identified as potential predictors of SN tumor involvement in patients with thin melanoma. In our current study, Breslow thickness was not significantly associated with SN tumor involvement in patients with thin melanoma. None of the six patients who had thin melanomas with a tumor-involved SN had evidence of regression or ulceration of the primary lesion, and only three of these patients had Clark’s level IV primary lesions. Information on mitotic rate and vertical growth phase was available for only a portion of the patients in our study, so these factors were not included in our current multivariate analysis. However, of the six patients who had thin melanomas with SN metastases, only one had a mitotic rate greater than zero and only four had evidence of vertical growth phase, so we feel it is unlikely these factors would have been valuable predictors of SN tumor involvement.

We suspect that with a larger sample size, advanced Clark’s level, ulceration, and even regression may have been significantly associated with SN tumor involvement. At the same time, we do not feel that the absence of these characteristics are acceptable exclusion criteria for LM/SL, as that approach would have missed three of the six metastases identified in this series. Even if the inclusion criteria for LM/SL were expanded to include all patients with lesions ≥0.75 mm thick, with lesions of Clark’s level IV or V, or with evidence of ulceration or regression, two of the six metastases in this study would have been missed.

This study was unable to detect significant predictors of SN tumor involvement by means of traditional clinical and histopathologic measures. More important, we were unable to identify predictors of tumor-free SN in patients with thin melanoma, using traditional clinical and histopathologic measures. As a result, we feel that investigators need to turn their efforts toward examining other histopathologic factors in the continued search for characteristics that may discriminate between "high risk" and "low risk" patients with thin melanoma.

There are limitations to all of the studies that have sought to identify risk factors for SN tumor involvement in patients with thin melanoma. All of the studies are small, retrospective, and from single institutions. Additionally, no group has implemented LM/SL for all patients with thin melanoma. As a result, there is an inherent selection bias in each of the studies, as each institution has attempted to identify patients with thin melanomas who might be "high risk" for nodal tumor involvement and preferentially offered LM/SL to these patients.30 For example, Bedrosian et al.23 performed LM/SL on patients with thin melanoma only if the primary lesion had evidence of vertical growth phase. Because of this selection bias, the true incidence of nodal tumor involvement in patients with thin melanoma remains unknown. While the incidence is likely higher than the 1% to 3% noted during the ELND era,16,28 it may not be as high as the 7% to 13% found in recent SN studies.27,31–34 At our institution, LM/SL is more likely to be offered to patients who have thin melanomas of advanced Clark’s level, ulceration, or regression. However, since many patients with thin melanoma present to our institution specifically because they desire LM/SL, this study includes many patients who did not demonstrate these histopathologic findings. Consequently, the rate of SN tumor involvement in patients with thin melanoma at our institution (4%) is lower than seen in other SN studies. While our study still suffers from some selection bias, we believe the incidence of SN tumor involvement in this study is more representative of the true incidence of SN tumor involvement when all patients with thin melanoma are considered.

Although we were unable to identify any risk factors for SN tumor involvement, we believe further prospective studies are still needed to determine which patients with thin melanomas are truly "high risk" for nodal disease. In the interim, we feel it is reasonable to use histopathologic characteristics that have historically been associated with an increased risk of recurrence and death as inclusion criteria for LM/SL. For now, we believe that patients with thin melanoma whose primary lesions do not demonstrate histopathologic features of concern should not be routinely offered LM/SL, unless they are under consideration for an adjuvant treatment trial or other study protocol. In contrast, until long-term prospective data are available, we will continue to offer LM/SL to patients with thin melanomas who demonstrate historical risk factors for recurrence and death, including advanced Clark’s level, ulceration, and regression.

FOOTNOTES

Received October 2, 2003; accepted July 5, 2004.

Address correspondence and reprint requests to: David W. Ollila, MD, Division of Surgical Oncology, Department of Surgery, 3010 Old Clinic Building, CB#7213, University of North Carolina, Chapel Hill, NC 27599–7213; Fax: 919-966-8806; e-mail: david_ollila{at}med.unc.edu.

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B. E. Wright, R. P. Scheri, X. Ye, M. B. Faries, R. R. Turner, R. Essner, and D. L. Morton
Importance of Sentinel Lymph Node Biopsy in Patients With Thin Melanoma
Arch Surg, September 1, 2008; 143(9): 892 - 900.
[Abstract] [Full Text] [PDF]

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 Ann. Surg. Oncol.Home page
I. Koskivuo, L. Talve, P. Vihinen, M. Maki, T. Vahlberg, and E. Suominen
Sentinel Lymph Node Biopsy in Cutaneous Melanoma: A Case-Control Study
Ann. Surg. Oncol., December 1, 2007; 14(12): 3566 - 3574.
[Abstract] [Full Text] [PDF]

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 Ann. Surg. Oncol.Home page
G. C. Karakousis, P. A. Gimotty, B. J. Czerniecki, D. E. Elder, R. Elenitsas, M. E. Ming, D. L. Fraker, D. Guerry, and F. R. Spitz
Regional Nodal Metastatic Disease Is the Strongest Predictor of Survival in Patients with Thin Vertical Growth Phase Melanomas: A Case for SLN Staging Biopsy in These Patients
Ann. Surg. Oncol., May 1, 2007; 14(5): 1596 - 1603.
[Abstract] [Full Text] [PDF]

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 Ann. Surg. Oncol.Home page
G. C. Karakousis, P. A. Gimotty, J. D. Botbyl, S. B. Kesmodel, D. E. Elder, R. Elenitsas, M. E. Ming, D. Guerry, D. L. Fraker, B. J. Czerniecki, et al.
Predictors of Regional Nodal Disease in Patients With Thin Melanomas
Ann. Surg. Oncol., April 1, 2006; 13(4): 533 - 541.
[Abstract] [Full Text] [PDF]

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M. I. Ross
Early-stage melanoma: staging criteria and prognostic modeling.
Clin. Cancer Res., April 1, 2006; 12(7): 2312s - 2319s.
[Abstract] [Full Text] [PDF]

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 Ann. Surg. Oncol.Home page
S. L. Wong, M. S. Brady, K. J. Busam, and D. G. Coit
Results of Sentinel Lymph Node Biopsy in Patients With Thin Melanoma
Ann. Surg. Oncol., March 1, 2006; 13(3): 302 - 309.
[Abstract] [Full Text] [PDF]

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 Ann. Surg. Oncol.Home page
J. Vaquerano, W. G. Kraybill, D. L. Driscoll, R. Cheney, and J. M. Kane III
American Joint Committee on Cancer Clinical Stage as a Selection Criterion for Sentinel Lymph Node Biopsy in Thin Melanoma
Ann. Surg. Oncol., February 1, 2006; 13(2): 198 - 204.
[Abstract] [Full Text] [PDF]

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