Sentinel Lymph Node Status is the Most Important Prognostic Factor in Patients With Melanoma of the Scalp

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1 The Laryngoscope VC 2013 The American Laryngological, Rhinological and Otological Society, Inc. Sentinel Lymph Node Status is the Most Important Prognostic Factor in Patients With Melanoma of the Scalp Zachary J. Cappello, BS; Adam C. Augenstein, MD; Kevin L. Potts, MD; Kelly M. McMasters, MD, PhD; Jeffrey M. Bumpous, MD Objectives/Hypothesis: To compare clinicopathologic and prognostic factors associated with scalp melanomas and nonscalp melanomas of the head and neck (H&N). Study Design: Post hoc analysis of the database from a multi-institutional, prospective, randomized study. Methods: Clinicopathologic factors were assessed and correlated with survival and recurrence. Univariate and multivariate analysis of prognostic factors affecting disease-free survival and overall survival were performed. Results: Of 405 patients with H&N melanomas 1.0 mm thickness, 109 patients had melanoma of the scalp. All were Caucasian (100%), with most being male (79.5%) with a mean age of 49.8 years. The mean thickness was 2.4 mm; 25% had signs of ulceration. Sentinel lymph node (SLN) positivity was seen in 20.9% of scalp melanoma patients, and was more likely in younger patients (44.7 vs years, P ¼.04) and in those with a thickness of 2 to 4 mm (P ¼.005). The incidence of locoregional and distant recurrence were similar. Overall survival for scalp melanoma patients was significantly impacted by SLN positivity (P ¼.03), whereas thickness and ulceration status predicted poorer survival in nonscalp melanoma patients (P ¼.005, P <.0001, respectively). Conclusions: In the Sunbelt Melanoma Trial, SLN status was the strongest predictor of overall survival in scalp melanoma. Tumor thickness and ulceration correlated with poorer overall survival in nonscalp H&N melanoma. The prognostic significance of SLN status in the H&N may vary with the melanoma site. Key Words: Head and neck carcinoma, scalp, Sunbelt Melanoma Trial, sentinel lymph nodes. Level of Evidence: 2c. Laryngoscope, 123: , 2013 INTRODUCTION The prognostic significance of many clinicopathologic factors in patients with melanoma is well established, including, age, gender, tumor thickness, ulceration, regional lymph node status, and distant metastasis. Controversy exists surrounding the primary melanoma site as an independent predictor of survival. Conflicting reports exist in the literature suggesting melanoma of the scalp portending a poorer prognosis compared to other anatomic sites, 1 3 whereas others have found the same to be true for the ear subsite. 4 A combination of head and neck (H&N) subsites in these evaluations further complicates interpretation of the data. Ultimately, debate still continues regarding the From the Division of Otolaryngology Head and Neck Surgery (Z.J.C., A.C.A., K.L.P., J.M.B.), and Division of Surgical Oncology (K.M.M.), Department of Surgery, University of Louisville School of Medicine, Louisville, Kentucky, U.S.A. Editor s Note: This Manuscript was accepted for publication September 20, Presented as a poster at the Combined Otolaryngology Society Meeting, Las Vegas, Nevada, U.S.A., April 28 May 2, The authors have no funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Jeffrey M. Bumpous, MD, Division of Otolaryngology, Brown Cancer Center, 3rd Floor, 529 South Jackson Street, Louisville, KY jeffrey.bumpous@louisville.edu DOI: /lary prognostic significance of the anatomic site among melanomas of the H&N. Sentinel lymph node (SLN) biopsy is increasingly integral to the surgical management of primary malignant melanoma, and has become a standard method of staging patients with cutaneous melanoma. 5 It allows accurate nodal staging that targets patients who may benefit from regional lymphadenectomy and systemic therapy. The SNL is defined as the first node in the regional basin the receives lymphatic drainage from the primary tumor. 6 Given the complex and multiple routes of lymphatic spread, including the nodes of the parotid, postauricular, suboccipital, posterior cervical, and jugulodigastric areas, 7 different clinicopathologic features affecting survival may be present in melanoma of the scalp compared to other anatomic sites within the H&N. This study sought to evaluate these factors as well as the prognosis of patients enrolled in the Sunbelt Melanoma Trial with scalp melanomas in comparison to nonscalp melanomas of the H&N. MATERIALS AND METHODS The Sunbelt Melanoma Trial is a multi-institutional, prospective, randomized study approved by the institutional review boards of the 79 involved centers in North America. The trial was designed to evaluate the role of adjuvant interferon alfa-2b in patients undergoing SLN biopsy with minimal nodal tumor burden. This study enrolled patients from June 1997 to October Of 3,533 patients registered, 405 patients were identified 1411

2 TABLE I. Sunbelt Melanoma Trial Head and Neck Site Incidence. Anatomic Site No. of Patients (%) Ear 59 (14.6) Face 117 (28.9) Neck 120 (29.6) Scalp 109 (26.9) with H&N melanomas. Eligible patients were aged 18 to 70 years with melanoma of 1.0-mm thickness and clinically uninvolved (N0) regional lymph nodes. Patients with more than one primary melanoma were excluded from the study, as were those who had already undergone wide local excision of the primary melanoma. Participating surgeons included otolaryngology-h&n surgeons, surgical oncologists, plastic surgeons, and general surgeons experienced with SLN biopsy for melanoma. After signing informed consent, patients underwent wide local excision of the primary melanoma and SLN biopsy using intradermal injection of technetium sulfur colloid around the primary tumor site. A lymphoscintigram was obtained to identify all draining nodal basins and intransit sentinel nodes preoperatively. A handheld gamma probe was used intraoperatively to guide SLN identification. Intradermal injection of isosulfan blue dye (1 to 5 ml) was performed in the majority of cases as well. The protocol allowed injection of radioactive colloid without blue dye injection, as this was the preferred method at some centers, and in some cases there were concerns regarding the cosmetic outcome of injecting isosulfan blue dye with potential long-term staining of the skin, especially for H&N melanomas. Although the protocol did not specify that blue dye alone (no radioactive colloid) should be used, this was done in a small number of cases. Those cases are included in the analyses. All blue nodes and all nodes 10% of the most radioactive or hottest node were harvested as SLNs. 6 SLNs were processed by conventional hematoxylin and eosin (H&E) staining at multiple levels, with at least five sections per block, along with two additional random sections for immunohistochemistry (IHC) of S100 protein. In addition, IHC for HMB-45, MART-1, or other markers was performed in a small number of centers. A central pathology review committee evaluated the first 10 cases from each participating institution, as well as all cases of SLN metastasis. Patients found to have an SLN with metastatic disease by H&E staining and/or IHC underwent completion lymph node dissection of the involved nodal basin(s). We then evaluated and analyzed these data with special emphasis on prognostic indicators of survival and recurrence. This included SLN status, tumor characteristics, and location. The evaluation of a set of possible prognostic indicators of survival and recurrence were fit using a Cox regression model. Additionally, similar models were fit for each of the location groups. Kaplan-Meier estimates of the survival function were also performed. The primary test of each of the possible prognostic variables is the test of the model coefficient from the Cox regression. To further evaluate the impact of the prognostic variables on the outcomes (and to mitigate problems arising from the rarity of the outcome events of interest), simple log-rank tests of survival and recurrence were conducted separately for each categorical variable. These tests were conducted to supplement the results of the Cox model. Conclusions about the association between prognostic variables and survival and recurrence should be drawn from the results of the Cox regression. All statistical analyses were conducted in the R software package (R version 2.6.2, The R Foundation for Statistical Computing, All hypothesis tests were performed at the.05 level of significance. RESULTS Of 405 total patients with melanoma of the H&N, 109 (26.9%) had melanoma of the scalp (Table I), and of these only 88 patients could be used due to incomplete datasets for several patients with scalp melanoma. A comparison of patients with scalp melanoma and those with nonscalp melanoma can be found in Table II. In addition, the average time to follow-up for patients was similar for both scalp and nonscalp melanoma groups (58.06 months and months , respectively). Of these scalp melanoma patients, the dominant characteristics included being male (79.5%) and TABLE II. Characteristics of Patients With Scalp Melanoma in the Sunbelt Melanoma Trial. Characteristic Scalp Melanomas Head and Neck Melanomas Age, mean 6 SD, yr Sex, No. (%) Male 70 (79.5) 210 (71.4).109 Female 18 (20.5) 84 (28.6).109 Race, No. (%) Caucasian 88 (100.0) 281(97.2).004 Hispanic 0 (0.0) 6 (2.1).013 Unknown 0 (0.0) 1 (0.3).351 Native American 0 (0.0) 1 (0.3).351 Ulceration, No. (%) Absent 65 (74.7) 200 (71.7).577 Present 22 (25.3) 79 (28.3).577 Lymphovascular invasion, No. (%) Absent 71 (86.6) 222 (92.5).153 Present 11 (13.4) 18 (7.5).153 SLN, No. (%) Negative 68 (79.1) 247 (88.5).049 Positive 18 (20.9) 32 (11.5).049 Melanoma subtype Other/unknown 17 (19.3) 64 (23.5).394 Nodular 24 (27.3) 82 (30.1).611 Superficial spreading 35 (39.8) 89 (32.7).232 Lentigo maligna 9 (10.2) 22 (8.1).563 Desmoplastic 0 (0.0) 15 (5.5).000 Spindle cell 3 (3.4) 0 (0.0) , No. (%) 56 (53.8) 179 (63.0) , No. (%) 35 (33.7) 75 (26.4).170 >4.00, No. (%) 13 (12.5) 30 (10.6).610 Mean6 SD Locoregional recurrence 13 (15.7) 12 (5.4).016 Distance recurrence 14 (16.9) 29 (13.0).406 SD ¼ standard deviation; SLN ¼ sentinel lymph node. 1412

3 TABLE III. Univariate and Multivariate Statistical Models of Overall Survival of Head and Neck Melanoma. TABLE V. Univariate and Multivariate Statistical Models of Disease-Free Survival of Head and Neck Melanoma. Log-Rank Hazard Ratio (95% CI) Cox Log-Rank Hazard Ratio (95% CI) Cox Scalp ( ).21 < Reference Reference ( ).39 > ( ).03 SLN positive ( ).08 Ulceration < ( ) <.0001 CI ¼ confidence interval; SLN ¼ sentinel lymph node. Caucasian of non-hispanic origin (100%), with an average age of 49.8 years. The most common histologic subtypes were superficial spreading (39.7%), nodular (27.3%), and lentigo maligna (10.2%). The average thickness was 2.4 mm (6 1.66), 22 (25%) were ulcerated, and 11 (13.4%) displayed lymphovascular invasion. SLN positivity was seen in 18 (20.9%) scalp melanoma patients biopsied. In addition, SNL positivity was more likely in younger patients (44.7 vs years, P ¼.04), and in those with a thickness of 2 to 4 mm (P ¼.005). The incidences of local and regional recurrence were too rare to determine significance (Table II). Ulcerated melanomas of the scalp and those with thicker tumors were at greater risk for distant recurrence, but there was no difference among the groups defined by location (scalp vs. nonscalp) and SLN status. A Cox regression model with the prognostic variables listed above in addition to the anatomic site in the H&N was formulated. This calculation showed that several variables were clearly not significant, and a reduced model was then designed excluding age, gender, histology, and lymphatic vascular invasion. Table III provides an analysis of overall survival using both univariate and multivariate statistical models, log-rank P values, and Cox P values, respectively. When the univariate statistical model was used, comparisons between scalp and nonscalp groups showed statistical significance with regard to thickness, SLN positivity, and ulceration. Using the univariate analysis, positivity in all Scalp ( ).47 SLN positive ( ).50 Ulceration ( ).09 Age N/A 0.99 ( ) Reference Reference ( ).20 > ( ).05 CI ¼ confidence interval; N/A ¼ not available; SLN ¼ sentinel lymph node. three prognostic factors portended a reduced overall survival in scalp melanoma versus nonscalp melanoma patients. Multivariate analysis (Cox regression) demonstrated that only ulceration was a statistically significant variable portending prognosis in scalp melanoma. When considering Tables III and IV together, it was observed that ulceration may be more important for the nonscalp patients than in scalp melanoma patients. Because the nonscalp patients dominated the sample, this partially explains the dominance of ulceration in the full sample analysis. Further, SLN status has an important impact on scalp patients, but not on nonscalp patients, in that scalp patients demonstrated reduced overall survival. Finally, thickness played an important role in predicting survival in the nonscalp patients, but was not important for the scalp patients. Table V provides an analysis of disease-free survival (DFS) using the same univariate and multivariate statistical models noted in overall survival analysis. Again, the univariate analysis showed statistical significance with regard to ulceration and thickness. In the multivariate analysis, however, the only prognostic factor to be of any significance was a thickness of >4.0 mm. This variation in the significance of the coefficients based on the model specification is in part a product of the low number of DFS events observed. However, using Tables V and VI together, it was noted that TABLE IV. Cox Regression Model for Overall Survival of Head and Neck Melanoma. TABLE VI. Cox Regression Model for Disease-Free Survival of Head and Neck Melanoma. Scalp Hazard Ratio, n ¼ 61 (95% CI) Hazard Ratio, n ¼ 235 (95% CI) Scalp Hazard Ratio (n ¼ 61) Hazard Ratio (n ¼ 235) Reference Reference ( ), P ¼ ( ), P ¼.13 > ( ), P ¼ ( ), P ¼.005 SLN positive 3.0 ( ), P ¼ ( ), P ¼.95 Ulceration 1.8 ( ), P ¼ ( ), P <.0001 CI ¼ confidence interval; SLN ¼ sentinel lymph node Reference Reference ( ), P ¼ ( ), P ¼.04 > ( ), P ¼ ( ), P ¼.004 SLN positive 2.1 ( ), P ¼ ( ), P ¼.78 Ulceration 0.7 ( ), P ¼ ( ), P ¼.04 SLN ¼ sentinel lymph node. 1413

4 Fig. 1. Kaplan-Meier disease free survival (DFS) curve by anatomic group and sentinel lymph node (SLN) positivity. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] ulceration and thickness played an important role in the nonscalp group. Kaplan-Meier survival curves for DFS are shown, detailing the variable impact of SLN positivity (Fig. 1), ulceration status (Fig. 2), and thickness (Fig. 3) in each group. Fig. 2. Kaplan-Meier disease free survival (DFS) curve by anatomic group and ulceration (Ulc) positivity. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] 1414 Fig. 3. Kaplan-Meier disease free survival (DFS) curve by anatomic group and thickness. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] DISCUSSION Our review found that ulcerated patients and those with thicker melanomas demonstrated a higher incidence of distant recurrences. There did not appear to be a difference in distant recurrences from scalp to nonscalp sites, but due to the low number of events in the scalp group, statistical comparison for this variable was not possible. Local and regional recurrences were rare events precluding statistical evaluation. As we compared overall survival of the scalp and nonscalp melanoma sites, both thickness and ulceration status seem to be more important in predicting survival for nonscalp patients relative to the scalp melanoma patients. The effect of ulceration status resulted in decreased survival when compared to SLN status and thickness. However, SLN status was the strongest predictor of overall survival in patients with melanoma of the scalp. thickness and ulceration significantly impacted DFS in nonscalp patients, but again the effect of ulceration seemed to dominate. In patients with scalp melanoma, SLN status was not a significant prognostic factor for DFS. The prognostic significance of the anatomic site has long been debated in the literature. Wanebo et al. assessed lesion location as a predictor of prognosis, finding the ear and scalp subsite to be a higher-risk location compared to the face and neck. 1 Their findings are consistent with other frequently cited studies. 3,7 The observation that the scalp subsite signified a poorer prognosis was further confirmed in other studies. In Ballantyne s large review of M. D. Anderson s experience, the scalp subsite alone was an independent predictor of poor survival, whereas the ear, face, and neck lacked such significance. 4 In Urist et al. s study, the scalp and neck subsite fared worse than the face or ear groups. 8 A recent multicenter review involving 590 patients stratified by anatomic site by Leong et al. with the Sentinel Lymph Node Working Group, again found tumors of the scalp to have the highest recurrence rate and a threetimes greater mortality than others sites in the H&N. 9 They suggested this might be due to early bloodborne metastasis. Lachiewicz et al., in an analysis of the Surveillance, Epidemiology, and End Results Program (SEER) compared the prognosis of patients with scalp or neck melanomas to other sites in a national database, controlling for known prognostic factors in over 50,000 patients. In an elegant analysis, they likewise concluded the scalp and neck site was worse than all other cutaneous sites, which included the trunk and extremities in addition to the face and ear. 10 The acronym BANS (upper back, posterior arm, posterior neck, and scalp), as it became known, was the first to classify anatomic location patterns of melanoma that

5 may influence survival. Many have challenged Day et al. 11 and many others findings that BANS and non-bans areas have prognostic differences. Cascinelli et al. were among the first to challenge this, finding in a review of 769 patients no prognostic relevance of melanoma location in the BANS region. 12 Gillgren et al. reviewed 496 patients in the Sweden National Cancer Registry and found that no anatomic site in the H&N was an independent predictor of survival. 13 Interestingly, the same database was analyzed in a previous time period by Ringborg et al., only to find melanomas of the ear, scalp, and neck subsites fared worse than those on the face. 14 The literature is filled with similar discrepancies on all sides. Our review of the Sunbelt Melanoma Trial found that across all events (recurrences, overall survival, and DFS), the location of the melanoma of the scalp in comparison to nonscalp sites within the H&N was not an independent risk factor. However, the clinicopathological triad of thickness, SLN status, and ulceration have a significant impact on overall survival and DFS. The relative importance of each of these may differ by anatomic location in the H&N. SLN biopsy provides further prognostic value in the management of primary malignant melanoma. However, the prognostic value of SLN biopsy for H&N melanoma has been a topic for debate. In a study undertaken by Carlson et al., it was concluded that SLN status, along with tumor thickness and site (scalp vs. nonscalp), was found to be significant in predicting the overall survival in patients with H&N melanoma. The 3-year overall survival rate for patients without SLN metastases was 82%, whereas patients with SLN metastases had only a 57% 3-year survival rate. 6 Similarly, in a study by Leong et al., from the SLN Working Group, it was observed that tumor site was an independent predictor of mortality; location on the scalp had a more than 3-fold (P <.001) greater mortality than tumors on the face. Tumor thickness was also an independent predictor of overall survival, and SLN status was the most important predictor of DFS in the multivariate analysis. 9 In a study by Doting et al., no significant difference was found in recurrence-free and overall survival between patients with tumor-positive and tumor-negative SLN. 15 Therefore, due to concerns about the safety of the procedure, Doting et al. concluded that SLN biopsy should not be used as a procedure when staging H&N melanoma patients. As with many large, multicenter trials, an inherent selection bias is present. The exclusion of thin melanomas from the study may further alter this, whereas the simultaneous exclusion of patients with clinically positive lymph nodes may likewise alter the conclusions regarding prognostic factors. More importantly, limitations in statistical analysis must be discussed. Several subjects had incomplete data; therefore, these were excluded in the calculation of the Cox regression models. This tended to bias the results by a factor proportional to the probability of having missing data. However, most missing data were not involving the prognostic factors we analyzed further (thickness, ulceration, SLN status); therefore, this is less concerning because most missing data were not related to survival or recurrence. Finally, it must be noted that the Sunbelt Melanoma Trial was not designed to answer the question that was addressed with this study, and also the different treatment arms of this study may have affected our data and conclusions. CONCLUSION In the Sunbelt Melanoma Trial, SLN status was the strongest predictor of overall survival in patients with melanoma of the scalp. Tumor thickness and ulceration correlated with overall survival in patients with nonscalp melanomas of the H&N. The prognostic significance of SLN status in the H&N may vary with the melanoma site, whereas site in and of itself does not correlate with survival when analyzing all anatomic sites in the H&N including scalp. BIBLIOGRAPHY 1. Wanebo HJ, Cooper PH, Young DV, Harpole DH, Kaiser DL. Prognostic factors in head and neck melanoma: effect of lesion location. Cancer 1988;62: Cole DJ, Mackay GJ, Walker BF, Wooden WA, Murray DR, Coleman JJ. Melanoma of the external ear. J Surg Oncol 1992;50: Byers RM, Smith JL, Russell N, Rosenberg V. Malignant melanoma of the external ear: review of 102 cases. Am J Surg 1980;140: Ballantyne AJ. Malignant melanoma of the skin of the head and neck: an analysis of 405 cases. 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