ORIGINAL ARTICLE
Recurrence of cutaneous melanoma of the head and neck after negative sentinel lymph node biopsy Melinda V. Davis–Malesevich, MD,1 Ryan Goepfert, MD,2 Mark Kubik, MD,1 Dianna B. Roberts, PhD,3 Jeffrey N. Myers, MD, PhD,3 Michael E. Kupferman, MD3* 1
Bobby R. Alford Department of Otolaryngology – Head and Neck Surgery, Baylor College of Medicine, Houston, Texas, 2Department of Otolaryngology – Head and Neck Surgery, University of California – San Francisco, San Francisco, California, 3Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Accepted 21 April 2014 Published online 11 July 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/hed.23718
ABSTRACT: Background. Sentinel lymph node biopsy remains controversial for cutaneous melanoma of the head and neck (CMHN). Incidence and factors associated with recurrence after negative sentinel lymph node biopsy have not been well delineated. Methods. Characteristics of 204 patients with head and neck melanoma who had a negative sentinel lymph node biopsy were studied. Main outcomes were overall survival and disease-free survival. Results. Recurrence developed in 45 patients (22%) with a median time to recurrence of 20.1 months. Five-year overall survival was 91.8% for patients without recurrence and 57.0% for those with recurrence. The overall regional recurrence rate was 8.8% (n 5 18) and was associated
INTRODUCTION Cutaneous melanoma is the fifth and sixth most common malignancy diagnosed in men and women, respectively, and its incidence is increasing more rapidly than any other cancer.1 Approximately 25% to 35% of newly diagnosed melanomas occur in the head and neck region, making the management of these lesions vitally important for the head and neck surgeon.2 Sentinel lymph node biopsy has emerged as an efficacious, minimally invasive, and prognostically significant method of staging melanomas by localizing and sampling the first echelon of draining lymph nodes for micrometastatic nests. This procedure identifies patients who have clinical stage I or II melanoma but who, in reality, have pathological stage III disease. Thus, sentinel lymph node biopsy allows the clinician to stratify patients based on prognosis and identify those individuals who may benefit from further therapy in the form of a completion lymph node dissection (CLND). Sentinel lymph node status is
*Corresponding author: M. E. Kupferman, The University of Texas MD Anderson Cancer Center, Department of Head and Neck Surgery, 1400 Pressler Street, Houston, TX 77030. E-mail: [email protected] This work was presented at the 2011 American Academy of OtolaryngologyHead and Neck Surgery Foundation Annual Meeting in San Francisco, California, September 11–14, 2011. Ehab Y. Hanna, MD, was recused from consideration of this manuscript.
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with Breslow thickness >2 mm and scalp location of the primary tumor. The false omission rate was 3.4%. Conclusion. For CMHN, regional recurrence after negative sentinel lymph node biopsy occurs at acceptably low rates relative to other sites, C 2014 Wiley Periodicals, although it is associated with adverse survival. V Inc. Head Neck 37: 1116–1121, 2015
KEY WORDS: melanoma, head and neck melanoma, cutaneous melanoma, melanoma recurrence, sentinel lymph node biopsy, falsenegative sentinel lymph node biopsy
the most powerful prognostic factor in intermediate thickness melanomas, with a 90.2% 5-year survival in those with negative sentinel lymph node biopsy versus 72.3% in those with positive sentinel nodes.3 Sentinel lymph node biopsy has been shown to be highly reliable in the hands of skilled surgeons and is generally accepted as the standard of care in intermediate thickness melanoma. Recurrence after negative sentinel lymph node biopsy can occur as local, in transit, regional, or distant disease. Although the impact on survival varies with the type of recurrence, the reduction in survival seen with recurrence is substantial.4 Despite the widespread acceptance of sentinel lymph node biopsy in the management of truncal and extremity melanoma, its application to cutaneous melanoma of the head and neck (CMHN) has been controversial. Several studies to date have found CMHN to be associated with a poorer prognosis and higher rate of recurrence relative to melanomas at other sites. The regional recurrence rate after negative sentinel lymph node biopsy for CMHN has been shown to range from 4% to 21%,5–7 and the corresponding regional recurrence rate for melanoma at all anatomic sites ranges from 2% to 4.7%.8–10 In the literature, this discrepancy has been attributed to several technical pitfalls for a false-negative sentinel lymph node biopsy. These include the following: poor radiotracer injection technique, insufficient time allotted for radiotracer to enter the primary echelon node, inability to localize the sentinel lymph node, and failure to detect
RECURRENCE
microscopic disease by the pathologist. Additionally, nodal drainage to the head and neck region is known to be rich and complex, making sentinel lymph node biopsy theoretically more challenging. Given the incidence of CMHN and the worse prognosis commonly associated with these lesions, understanding the rate of recurrence and the patient population at risk is extremely important. Unfortunately, most published data on recurrence after negative sentinel lymph node biopsy include primarily truncal and limb melanomas, and, thus, translation of these findings to the more complex clinical behavior of head and neck melanomas is difficult. The purposes of this study were to delineate prognostic factors and determine survival among patients with a negative sentinel lymph node biopsy.
PATIENTS AND METHODS After MD Anderson Cancer Center Institutional Review Board approval, a review of the records of patients with CMHN treated in the Department of Head and Neck Surgery between January 2000 and June 2009 was performed. Two hundred four patients were identified with CMHN who underwent successful sentinel lymph node biopsy (146 men and 58 women; mean age 58.1 years). Inclusion criteria included pathology-proven melanoma of Breslow thickness >1 mm, or Breslow thickness 1 mm was associated with local recurrence, distant metastasis, and decreased survival at 3-year and 5-year follow-ups. Breslow thickness >2 mm was 1 of 2 factors predictive of regional recurrence. Clark level 5 predicted local recurrence and Clark level >4 was associated with distant metastasis. Neither radial nor vertical growth was shown to have any correlation with recurrence. Tumor mitotic rate was not significantly associated with recurrence but did portend decreased survival at both 3 and 5 years, particularly when patients had >6 mitoses in their tumors (Figure 1A and 1B). Perineural invasion (PNI) of the primary tumor was associated with a higher incidence of local recurrence (p 5 .01). Of all local, regional, and distant recurrences, 7 (16.7%) exhibited PNI on pathologic analysis. We observed 20 local recurrences in this study and 4 (20.0%) occurred in the setting of PNI. PNI had no bearing on 1118
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For the entire cohort, the 3-year survival rate was 91%, and the 5-year survival rate was 77.3%. In those patients who had no recurrence after negative sentinel lymph node TABLE 2. Results of univariate analysis for predictors of survival outcomes.
Variables
Concomitant comorbidity Yes No Other malignancy Yes No Breslow tumor depth >1 mm 1 mm Ulceration Yes No Mitotic figures >6 0–6
No. of patients
% dead at 5 y*
36 167
37.1 12.0
66 135
25.2 11.9
133 65
20.9 8.4
45 146
27.2 12.4
29 146
34.8 13.4
Log-rank p value
.00010 .00034 .00235 .03322 .03084
* From Kaplan–Meier plots. The figures in bold indicate statistical significance.
RECURRENCE
AFTER NEGATIVE SENTINEL LYMPH NODE BIOPSY
TABLE 3. Results of univariate analysis for predictors of recurrence type. Local recurrence
Variables
Scalp primary site Yes No Breslow tumor depth >2 mm 2 mm Breslow tumor depth >1 mm 1 mm Perineural involvement Yes No Ulceration Yes No
No. of patients
% with local recurrence at 5 y*
40 164
13.1 9.7
65 133
17.7 7.6
133 65
14.9 3.1
10 170
49.4 8.4
45 146
9.5 9.9
Log-rank p value
Regional recurrence % with regional recurrence at 5 y*
.48633
Log-rank p value
Distant metastasis % with distant metastasis at 5 y*
.00060 22.1 5.4
.20045
.08023 20.0 11.6
.03409 14.9 4.4
.05204
.00318 23.7 8.1
.14924 10.4 3.3
.00139
.00079 19.1 1.8
.94742 10.0 10.3
.62784
.11789 33.3 12.6
.07531 17.7 7.2
Log-rank p value
.00398 26.3 9.7
* From Kaplan–Meier plots The figures in bold indicate statistical significance.
biopsy, 5-year overall survival was 91.8%, whereas the 5year overall survival for those who recurred was 57.0% (log-rank p < .00001; Figure 2). We found the overall survival plots to be significantly worse among those patients who recurred systemically (p 5 .01002) or had multiple recurrences (p 5 .00761), compared to those who recurred regionally (see Figure 3). The median follow-up interval between the end of treatment for initial disease to last contact was 59.8 months for patients who did not have recurrences or die, and 76.9% of patients were recurrence-free at 5 years (see Figure 4).
DISCUSSION Sentinel lymph node biopsy has been validated in the literature and is currently the standard of care for
intermediate thickness melanomas and for a subset of high-risk thin melanomas. Among those with a negative sentinel lymph node biopsy, the negative predictive value exceeds 95% and the prognosis is excellent.4,11 However, there is a small but defined subset of patients destined for recurrence and disseminated disease secondary to aggressive tumor biology. In this study, we identified distinct clinical and pathological variables that were predictive of regional recurrence after a negative sentinel lymph node biopsy, which was associated with unfavorable prognosis. Sentinel lymph node biopsy for CMHN is effective and provides important prognostic information, and regional recurrence after a negative sentinel lymph node biopsy is uncommon.1,4 However, among patients whose disease recurs after a negative sentinel lymph node biopsy,
FIGURE 1. (A) Survival outcome by Kaplan–Meier curves developed for patients with and without mitoses present in their melanomas (group 0mitoses absent, group 1-mitoses present). (B) Survival outcome by Kaplan–Meier curves developed for patients with and without >6 mitoses present in their melanomas. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
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TABLE 4. Sites of regional recurrence after negative sentinel lymph node biopsy. Level
No. of patients
Pre-auricular Parotid Level I Level II Level III Level IV Level V
1 11 4 5 2 2 20
whether regionally or distantly, the impact on survival is substantial. In our study, 5-year survival among those who were disease-free after a negative sentinel lymph node biopsy was 91.8%, whereas the survival rate among those who developed any form of recurrence was 57.0% at 5 years. These findings are in alignment with other studies that found that those patients who experienced recurrence after negatively sentinel lymph node biopsy had a 5-year survival of 68% compared to 98% for those who did not have recurrence.12 Head and neck location of a cutaneous melanoma has been shown to portend worse survival.6,7,9 The incidence of sentinel node positivity or nodal disease at diagnosis, however, is no different between CMHN and melanoma at other sites.11,13 Thus, many studies have proposed the reduced survival is directly related to elevated rates of recurrence seen with CMHN. In a study by Jones et al4 of 500 patients with melanomas at all sites, head and neck location of the primary was the strongest predictor of all forms of recurrence, and head and neck melanomas were associated with a net recurrence rate of 42.2%. In the most comprehensive systemic review of regional recurrence after sentinel lymph node biopsy, de Rosa et al5 reported the mean false-negative rate for head and neck melanoma to be 20.4%. However, a recent singleinstitution study of 353 patients with CMHN reported a false-negative rate of 3.4%, comparable to rates of nonhead and neck melanoma.11 The overall false omission
FIGURE 2. Survival outcome by Kaplan–Meier curves developed for overall survival in patients with and without recurrence of their disease
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FIGURE 3. Survival outcomes based on the type of recurrence.
rate for sentinel lymph node biopsy in the head and neck, which is the rate of regional recurrence after a negative sentinel lymph node biopsy, has been estimated to approximately 9% across multiple studies.11 However, in our study, although 8.8% of patients developed regional recurrence, we observed a false omission rate of 3.4%. These results compare favorably across other published studies from both head and neck and non–head and neck sites, suggesting that sentinel lymph node biopsy is an accurate procedure for predicting metastatic CMHN. Interestingly, although the data are small, regional failure alone was not associated with adverse outcomes, suggesting that these patients can be successfully salvaged, even in the face of a false-negative sentinel lymph node biopsy.
FIGURE 4. Disease-free interval among patients with negative sentinel lymph node biopsy. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
RECURRENCE
Risk factors for developing a recurrence after negative sentinel lymph node biopsy for CMHN are, thus, largely unclear, so we sought to identify features predictive of all types of recurrence in this unique population. Reported local recurrence rates for truncal/extremity melanoma range from 3% to 4%,4,14 yet our data revealed that nearly 10% of patients recurred as local or in-transit disease. Predictors of local recurrence included Breslow thickness >1 mm, Clark level 5, and PNI. On univariate analysis, only Breslow thickness >2 mm and primary location of the melanoma on the scalp predicted regional recurrence. Breslow thickness is an established predictor of regional recurrence and has been observed in several studies to date.8,9 The scalp location of the primary tumor correlated with elevated rates of regional recurrence, which is consistent with several other studies that have demonstrated increased mortality, recurrence rate, and rate of sentinel lymph node positivity associated with scalp melanomas.15–17 In the literature, analysis of completion lymphadenectomy specimens for scalp melanomas has shown a particularly erratic, unpredictable lymphatic spread with a high tendency to metastasize to the contralateral neck.18 Of the 40 scalp melanomas in this study, 22.2% recurred regionally, and scalp location was the only factor aside from Breslow thickness predictive of regional failure. Scalp melanomas historically are associated with a worse prognosis,15–17 and yet there is no literature to suggest that a scalp primary site confers an elevated risk of distant metastasis. Based upon this data, one could hypothesize that the increased mortality for scalp melanomas may be due to a failure of locoregional control, as we observed in this study. The increased complexity and unpredictable nature of lymphatic drainage from this subsite is further supported by our finding that these tumors map, on average, to 6 nodal basins in the head and neck, compared to 3.4 basins (p 5 .0004) in other head and neck sites. Analyses of larger datasets will be needed to determine if more aggressive initial treatment of these patients is warranted. Recurrence in the form of distant metastases occurs at a rate of 5% to 7.4% for all anatomic sites.4,8 However, in this cohort, we found that distant recurrences arose in 12.3% of patients. On univariate analysis, we found independent predictors for distant recurrence to include ulceration, Breslow thickness >1 mm, and Clark level IV to V. Although ulceration was predictive of distant metastasis and survival, there was no correlation with the rates of locoregional recurrence. Ulceration may reflect a more biologically aggressive tumor with a tendency to enter the vasculature and spread hematogenously, as opposed to lymphatic metastases. In the present study, those patients with high-risk ulcerative melanomas failed distantly in nearly 25% of cases, often in the absence of nodal failure. The role of adjuvant therapy in these patients is currently under investigation. A number of limitations in this study warrant comment. First, the limited number of patients in the study limits its power, and although this is one of the largest cohorts of patients with CMHN with negative sentinel lymph node biopsies, the limited number of recurrences makes drawing conclusions challenging. Second, this study was performed in a high volume, tertiary cancer referral center
AFTER NEGATIVE SENTINEL LYMPH NODE BIOPSY
with a possible selection bias toward higher risk melanomas, which may overestimate true population rates of recurrence. Third, the number of lymph nodes harvested and the total number of regional sites accessed were not specifically analyzed in this study. Future studies may include analyzing the risk of regional recurrence vis-a-vis the number of lymph nodes sampled at the time of sentinel lymph node biopsy. In conclusion, our experience suggests that recurrence after a negative sentinel lymph node biopsy is uncommon in the head and neck. As has been identified in other series, we found elevated rates of local, regional, and distant recurrence (9.8%, 8.8%, and 12.2%, respectively) relative to melanoma at all sites. We found that lesions greater than 2 mm thickness or scalp location were associated with an increased risk of regional recurrence after a negative sentinel lymph node biopsy. These recurrences have significant prognostic importance, and we found a 30% reduction in 5-year survival for those patients who suffered any form of recurrence. Specific pathologic features may identify the at-risk population who may benefit from treatment intensification to limit recurrence and mortality.
REFERENCES 1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin 2012;62:10–29. 2. Younes MN, Myers JN. Melanoma of the head and neck: current concepts in staging, diagnosis, and management. Surg Oncol Clin N Am 2004;13: 201–229. 3. Morton DL, Cochran AJ, Thompson JF, et al. Sentinel node biopsy for early-stage melanoma: accuracy and morbidity in MSLT-I, an international multicenter trial. Ann Surg 2005;242:302–311; discussion 311–313. 4. Jones EL, Jones TS, Pearlman NW, et al. Long-term follow-up and survival of patients following a recurrence of melanoma after a negative sentinel lymph node biopsy result. JAMA Surg 2013;148:456–461. 5. de Rosa N, Lyman GH, Silbermins D, et al. Sentinel node biopsy for head and neck melanoma: a systematic review. Otolaryngol Head Neck Surg 2011;145:375–382. 6. Gomez–Rivera F, Santillan A, McMurphey AB, et al. Sentinel node biopsy in patients with cutaneous melanoma of the head and neck: recurrence and survival study. Head Neck 2008;30:1284–1294. 7. Miller MW, Vetto JT, Monroe MM, Weerasinghe R, Andersen PE, Gross ND. False-negative sentinel lymph node biopsy in head and neck melanoma. Otolaryngol Head Neck Surg 2011;145:606–611. 8. Carlson GW, Page AJ, Cohen C, et al. Regional recurrence after negative sentinel lymph node biopsy for melanoma. Ann Surg 2008;248:378–386. 9. Scoggins CR, Martin RC, Ross MI, et al. Factors associated with falsenegative sentinel lymph node biopsy in melanoma patients. Ann Surg Oncol 2010;17:709–717. 10. Schmalbach CE, Nussenbaum B, Rees RS, Schwartz J, Johnson TM, Bradford CR. Reliability of sentinel lymph node mapping with biopsy for head and neck cutaneous melanoma. Arch Otolaryngol Head Neck Surg 2003;129:61–65. 11. Erman AB, Collar RM, Griffith KA, et al. Sentinel lymph node biopsy is accurate and prognostic in head and neck melanoma. Cancer 2012;118: 1040–1047. 12. Saltman BE, Ganly I, Patel SG, et al. Prognostic implication of sentinel lymph node biopsy in cutaneous head and neck melanoma. Head Neck 2010;32:1686–1692. 13. Faries MB, Wanek LA, Elashoff D, Wright BE, Morton DL. Predictors of occult nodal metastasis in patients with thin melanoma. Arch Surg 2010; 145:137–142. 14. Karakousis CP, Balch CM, Urist MM, Ross MM, Smith TJ, Bartolucci AA. Local recurrence in malignant melanoma: long-term results of the multiinstitutional randomized surgical trial. Ann Surg Oncol 1996;3:446–452. 15. Lachiewicz AM, Berwick M, Wiggins CL, Thomas NE. Survival differences between patients with scalp or neck melanoma and those with melanoma of other sites in the Surveillance, Epidemiology, and End Results (SEER) program. Arch Dermatol 2008;144:515–521. 16. Larson DL, Larson JD. Head and neck melanoma. Clin Plast Surg 2010;37: 73–77. 17. Tseng WH, Martinez SR. Tumor location predicts survival in cutaneous head and neck melanoma. J Surg Res 2011;167:192–198. 18. Pathak I, O’Brien CJ, Petersen–Schaeffer K, et al. Do nodal metastases from cutaneous melanoma of the head and neck follow a clinically predictable pattern? Head Neck 2001;23:785–790.
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Recurrence of cutaneous melanoma of the head and neck after negative sentinel lymph node biopsy Melinda V. Davis–Malesevich, MD,1 Ryan Goepfert, MD,2 Mark Kubik, MD,1 Dianna B. Roberts, PhD,3 Jeffrey N. Myers, MD, PhD,3 Michael E. Kupferman, MD3* 1
Bobby R. Alford Department of Otolaryngology – Head and Neck Surgery, Baylor College of Medicine, Houston, Texas, 2Department of Otolaryngology – Head and Neck Surgery, University of California – San Francisco, San Francisco, California, 3Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Accepted 21 April 2014 Published online 11 July 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/hed.23718
ABSTRACT: Background. Sentinel lymph node biopsy remains controversial for cutaneous melanoma of the head and neck (CMHN). Incidence and factors associated with recurrence after negative sentinel lymph node biopsy have not been well delineated. Methods. Characteristics of 204 patients with head and neck melanoma who had a negative sentinel lymph node biopsy were studied. Main outcomes were overall survival and disease-free survival. Results. Recurrence developed in 45 patients (22%) with a median time to recurrence of 20.1 months. Five-year overall survival was 91.8% for patients without recurrence and 57.0% for those with recurrence. The overall regional recurrence rate was 8.8% (n 5 18) and was associated
INTRODUCTION Cutaneous melanoma is the fifth and sixth most common malignancy diagnosed in men and women, respectively, and its incidence is increasing more rapidly than any other cancer.1 Approximately 25% to 35% of newly diagnosed melanomas occur in the head and neck region, making the management of these lesions vitally important for the head and neck surgeon.2 Sentinel lymph node biopsy has emerged as an efficacious, minimally invasive, and prognostically significant method of staging melanomas by localizing and sampling the first echelon of draining lymph nodes for micrometastatic nests. This procedure identifies patients who have clinical stage I or II melanoma but who, in reality, have pathological stage III disease. Thus, sentinel lymph node biopsy allows the clinician to stratify patients based on prognosis and identify those individuals who may benefit from further therapy in the form of a completion lymph node dissection (CLND). Sentinel lymph node status is
*Corresponding author: M. E. Kupferman, The University of Texas MD Anderson Cancer Center, Department of Head and Neck Surgery, 1400 Pressler Street, Houston, TX 77030. E-mail: [email protected] This work was presented at the 2011 American Academy of OtolaryngologyHead and Neck Surgery Foundation Annual Meeting in San Francisco, California, September 11–14, 2011. Ehab Y. Hanna, MD, was recused from consideration of this manuscript.
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with Breslow thickness >2 mm and scalp location of the primary tumor. The false omission rate was 3.4%. Conclusion. For CMHN, regional recurrence after negative sentinel lymph node biopsy occurs at acceptably low rates relative to other sites, C 2014 Wiley Periodicals, although it is associated with adverse survival. V Inc. Head Neck 37: 1116–1121, 2015
KEY WORDS: melanoma, head and neck melanoma, cutaneous melanoma, melanoma recurrence, sentinel lymph node biopsy, falsenegative sentinel lymph node biopsy
the most powerful prognostic factor in intermediate thickness melanomas, with a 90.2% 5-year survival in those with negative sentinel lymph node biopsy versus 72.3% in those with positive sentinel nodes.3 Sentinel lymph node biopsy has been shown to be highly reliable in the hands of skilled surgeons and is generally accepted as the standard of care in intermediate thickness melanoma. Recurrence after negative sentinel lymph node biopsy can occur as local, in transit, regional, or distant disease. Although the impact on survival varies with the type of recurrence, the reduction in survival seen with recurrence is substantial.4 Despite the widespread acceptance of sentinel lymph node biopsy in the management of truncal and extremity melanoma, its application to cutaneous melanoma of the head and neck (CMHN) has been controversial. Several studies to date have found CMHN to be associated with a poorer prognosis and higher rate of recurrence relative to melanomas at other sites. The regional recurrence rate after negative sentinel lymph node biopsy for CMHN has been shown to range from 4% to 21%,5–7 and the corresponding regional recurrence rate for melanoma at all anatomic sites ranges from 2% to 4.7%.8–10 In the literature, this discrepancy has been attributed to several technical pitfalls for a false-negative sentinel lymph node biopsy. These include the following: poor radiotracer injection technique, insufficient time allotted for radiotracer to enter the primary echelon node, inability to localize the sentinel lymph node, and failure to detect
RECURRENCE
microscopic disease by the pathologist. Additionally, nodal drainage to the head and neck region is known to be rich and complex, making sentinel lymph node biopsy theoretically more challenging. Given the incidence of CMHN and the worse prognosis commonly associated with these lesions, understanding the rate of recurrence and the patient population at risk is extremely important. Unfortunately, most published data on recurrence after negative sentinel lymph node biopsy include primarily truncal and limb melanomas, and, thus, translation of these findings to the more complex clinical behavior of head and neck melanomas is difficult. The purposes of this study were to delineate prognostic factors and determine survival among patients with a negative sentinel lymph node biopsy.
PATIENTS AND METHODS After MD Anderson Cancer Center Institutional Review Board approval, a review of the records of patients with CMHN treated in the Department of Head and Neck Surgery between January 2000 and June 2009 was performed. Two hundred four patients were identified with CMHN who underwent successful sentinel lymph node biopsy (146 men and 58 women; mean age 58.1 years). Inclusion criteria included pathology-proven melanoma of Breslow thickness >1 mm, or Breslow thickness 1 mm was associated with local recurrence, distant metastasis, and decreased survival at 3-year and 5-year follow-ups. Breslow thickness >2 mm was 1 of 2 factors predictive of regional recurrence. Clark level 5 predicted local recurrence and Clark level >4 was associated with distant metastasis. Neither radial nor vertical growth was shown to have any correlation with recurrence. Tumor mitotic rate was not significantly associated with recurrence but did portend decreased survival at both 3 and 5 years, particularly when patients had >6 mitoses in their tumors (Figure 1A and 1B). Perineural invasion (PNI) of the primary tumor was associated with a higher incidence of local recurrence (p 5 .01). Of all local, regional, and distant recurrences, 7 (16.7%) exhibited PNI on pathologic analysis. We observed 20 local recurrences in this study and 4 (20.0%) occurred in the setting of PNI. PNI had no bearing on 1118
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For the entire cohort, the 3-year survival rate was 91%, and the 5-year survival rate was 77.3%. In those patients who had no recurrence after negative sentinel lymph node TABLE 2. Results of univariate analysis for predictors of survival outcomes.
Variables
Concomitant comorbidity Yes No Other malignancy Yes No Breslow tumor depth >1 mm 1 mm Ulceration Yes No Mitotic figures >6 0–6
No. of patients
% dead at 5 y*
36 167
37.1 12.0
66 135
25.2 11.9
133 65
20.9 8.4
45 146
27.2 12.4
29 146
34.8 13.4
Log-rank p value
.00010 .00034 .00235 .03322 .03084
* From Kaplan–Meier plots. The figures in bold indicate statistical significance.
RECURRENCE
AFTER NEGATIVE SENTINEL LYMPH NODE BIOPSY
TABLE 3. Results of univariate analysis for predictors of recurrence type. Local recurrence
Variables
Scalp primary site Yes No Breslow tumor depth >2 mm 2 mm Breslow tumor depth >1 mm 1 mm Perineural involvement Yes No Ulceration Yes No
No. of patients
% with local recurrence at 5 y*
40 164
13.1 9.7
65 133
17.7 7.6
133 65
14.9 3.1
10 170
49.4 8.4
45 146
9.5 9.9
Log-rank p value
Regional recurrence % with regional recurrence at 5 y*
.48633
Log-rank p value
Distant metastasis % with distant metastasis at 5 y*
.00060 22.1 5.4
.20045
.08023 20.0 11.6
.03409 14.9 4.4
.05204
.00318 23.7 8.1
.14924 10.4 3.3
.00139
.00079 19.1 1.8
.94742 10.0 10.3
.62784
.11789 33.3 12.6
.07531 17.7 7.2
Log-rank p value
.00398 26.3 9.7
* From Kaplan–Meier plots The figures in bold indicate statistical significance.
biopsy, 5-year overall survival was 91.8%, whereas the 5year overall survival for those who recurred was 57.0% (log-rank p < .00001; Figure 2). We found the overall survival plots to be significantly worse among those patients who recurred systemically (p 5 .01002) or had multiple recurrences (p 5 .00761), compared to those who recurred regionally (see Figure 3). The median follow-up interval between the end of treatment for initial disease to last contact was 59.8 months for patients who did not have recurrences or die, and 76.9% of patients were recurrence-free at 5 years (see Figure 4).
DISCUSSION Sentinel lymph node biopsy has been validated in the literature and is currently the standard of care for
intermediate thickness melanomas and for a subset of high-risk thin melanomas. Among those with a negative sentinel lymph node biopsy, the negative predictive value exceeds 95% and the prognosis is excellent.4,11 However, there is a small but defined subset of patients destined for recurrence and disseminated disease secondary to aggressive tumor biology. In this study, we identified distinct clinical and pathological variables that were predictive of regional recurrence after a negative sentinel lymph node biopsy, which was associated with unfavorable prognosis. Sentinel lymph node biopsy for CMHN is effective and provides important prognostic information, and regional recurrence after a negative sentinel lymph node biopsy is uncommon.1,4 However, among patients whose disease recurs after a negative sentinel lymph node biopsy,
FIGURE 1. (A) Survival outcome by Kaplan–Meier curves developed for patients with and without mitoses present in their melanomas (group 0mitoses absent, group 1-mitoses present). (B) Survival outcome by Kaplan–Meier curves developed for patients with and without >6 mitoses present in their melanomas. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
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TABLE 4. Sites of regional recurrence after negative sentinel lymph node biopsy. Level
No. of patients
Pre-auricular Parotid Level I Level II Level III Level IV Level V
1 11 4 5 2 2 20
whether regionally or distantly, the impact on survival is substantial. In our study, 5-year survival among those who were disease-free after a negative sentinel lymph node biopsy was 91.8%, whereas the survival rate among those who developed any form of recurrence was 57.0% at 5 years. These findings are in alignment with other studies that found that those patients who experienced recurrence after negatively sentinel lymph node biopsy had a 5-year survival of 68% compared to 98% for those who did not have recurrence.12 Head and neck location of a cutaneous melanoma has been shown to portend worse survival.6,7,9 The incidence of sentinel node positivity or nodal disease at diagnosis, however, is no different between CMHN and melanoma at other sites.11,13 Thus, many studies have proposed the reduced survival is directly related to elevated rates of recurrence seen with CMHN. In a study by Jones et al4 of 500 patients with melanomas at all sites, head and neck location of the primary was the strongest predictor of all forms of recurrence, and head and neck melanomas were associated with a net recurrence rate of 42.2%. In the most comprehensive systemic review of regional recurrence after sentinel lymph node biopsy, de Rosa et al5 reported the mean false-negative rate for head and neck melanoma to be 20.4%. However, a recent singleinstitution study of 353 patients with CMHN reported a false-negative rate of 3.4%, comparable to rates of nonhead and neck melanoma.11 The overall false omission
FIGURE 2. Survival outcome by Kaplan–Meier curves developed for overall survival in patients with and without recurrence of their disease
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FIGURE 3. Survival outcomes based on the type of recurrence.
rate for sentinel lymph node biopsy in the head and neck, which is the rate of regional recurrence after a negative sentinel lymph node biopsy, has been estimated to approximately 9% across multiple studies.11 However, in our study, although 8.8% of patients developed regional recurrence, we observed a false omission rate of 3.4%. These results compare favorably across other published studies from both head and neck and non–head and neck sites, suggesting that sentinel lymph node biopsy is an accurate procedure for predicting metastatic CMHN. Interestingly, although the data are small, regional failure alone was not associated with adverse outcomes, suggesting that these patients can be successfully salvaged, even in the face of a false-negative sentinel lymph node biopsy.
FIGURE 4. Disease-free interval among patients with negative sentinel lymph node biopsy. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
RECURRENCE
Risk factors for developing a recurrence after negative sentinel lymph node biopsy for CMHN are, thus, largely unclear, so we sought to identify features predictive of all types of recurrence in this unique population. Reported local recurrence rates for truncal/extremity melanoma range from 3% to 4%,4,14 yet our data revealed that nearly 10% of patients recurred as local or in-transit disease. Predictors of local recurrence included Breslow thickness >1 mm, Clark level 5, and PNI. On univariate analysis, only Breslow thickness >2 mm and primary location of the melanoma on the scalp predicted regional recurrence. Breslow thickness is an established predictor of regional recurrence and has been observed in several studies to date.8,9 The scalp location of the primary tumor correlated with elevated rates of regional recurrence, which is consistent with several other studies that have demonstrated increased mortality, recurrence rate, and rate of sentinel lymph node positivity associated with scalp melanomas.15–17 In the literature, analysis of completion lymphadenectomy specimens for scalp melanomas has shown a particularly erratic, unpredictable lymphatic spread with a high tendency to metastasize to the contralateral neck.18 Of the 40 scalp melanomas in this study, 22.2% recurred regionally, and scalp location was the only factor aside from Breslow thickness predictive of regional failure. Scalp melanomas historically are associated with a worse prognosis,15–17 and yet there is no literature to suggest that a scalp primary site confers an elevated risk of distant metastasis. Based upon this data, one could hypothesize that the increased mortality for scalp melanomas may be due to a failure of locoregional control, as we observed in this study. The increased complexity and unpredictable nature of lymphatic drainage from this subsite is further supported by our finding that these tumors map, on average, to 6 nodal basins in the head and neck, compared to 3.4 basins (p 5 .0004) in other head and neck sites. Analyses of larger datasets will be needed to determine if more aggressive initial treatment of these patients is warranted. Recurrence in the form of distant metastases occurs at a rate of 5% to 7.4% for all anatomic sites.4,8 However, in this cohort, we found that distant recurrences arose in 12.3% of patients. On univariate analysis, we found independent predictors for distant recurrence to include ulceration, Breslow thickness >1 mm, and Clark level IV to V. Although ulceration was predictive of distant metastasis and survival, there was no correlation with the rates of locoregional recurrence. Ulceration may reflect a more biologically aggressive tumor with a tendency to enter the vasculature and spread hematogenously, as opposed to lymphatic metastases. In the present study, those patients with high-risk ulcerative melanomas failed distantly in nearly 25% of cases, often in the absence of nodal failure. The role of adjuvant therapy in these patients is currently under investigation. A number of limitations in this study warrant comment. First, the limited number of patients in the study limits its power, and although this is one of the largest cohorts of patients with CMHN with negative sentinel lymph node biopsies, the limited number of recurrences makes drawing conclusions challenging. Second, this study was performed in a high volume, tertiary cancer referral center
AFTER NEGATIVE SENTINEL LYMPH NODE BIOPSY
with a possible selection bias toward higher risk melanomas, which may overestimate true population rates of recurrence. Third, the number of lymph nodes harvested and the total number of regional sites accessed were not specifically analyzed in this study. Future studies may include analyzing the risk of regional recurrence vis-a-vis the number of lymph nodes sampled at the time of sentinel lymph node biopsy. In conclusion, our experience suggests that recurrence after a negative sentinel lymph node biopsy is uncommon in the head and neck. As has been identified in other series, we found elevated rates of local, regional, and distant recurrence (9.8%, 8.8%, and 12.2%, respectively) relative to melanoma at all sites. We found that lesions greater than 2 mm thickness or scalp location were associated with an increased risk of regional recurrence after a negative sentinel lymph node biopsy. These recurrences have significant prognostic importance, and we found a 30% reduction in 5-year survival for those patients who suffered any form of recurrence. Specific pathologic features may identify the at-risk population who may benefit from treatment intensification to limit recurrence and mortality.
REFERENCES 1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin 2012;62:10–29. 2. Younes MN, Myers JN. Melanoma of the head and neck: current concepts in staging, diagnosis, and management. Surg Oncol Clin N Am 2004;13: 201–229. 3. Morton DL, Cochran AJ, Thompson JF, et al. Sentinel node biopsy for early-stage melanoma: accuracy and morbidity in MSLT-I, an international multicenter trial. Ann Surg 2005;242:302–311; discussion 311–313. 4. Jones EL, Jones TS, Pearlman NW, et al. Long-term follow-up and survival of patients following a recurrence of melanoma after a negative sentinel lymph node biopsy result. JAMA Surg 2013;148:456–461. 5. de Rosa N, Lyman GH, Silbermins D, et al. Sentinel node biopsy for head and neck melanoma: a systematic review. Otolaryngol Head Neck Surg 2011;145:375–382. 6. Gomez–Rivera F, Santillan A, McMurphey AB, et al. Sentinel node biopsy in patients with cutaneous melanoma of the head and neck: recurrence and survival study. Head Neck 2008;30:1284–1294. 7. Miller MW, Vetto JT, Monroe MM, Weerasinghe R, Andersen PE, Gross ND. False-negative sentinel lymph node biopsy in head and neck melanoma. Otolaryngol Head Neck Surg 2011;145:606–611. 8. Carlson GW, Page AJ, Cohen C, et al. Regional recurrence after negative sentinel lymph node biopsy for melanoma. Ann Surg 2008;248:378–386. 9. Scoggins CR, Martin RC, Ross MI, et al. Factors associated with falsenegative sentinel lymph node biopsy in melanoma patients. Ann Surg Oncol 2010;17:709–717. 10. Schmalbach CE, Nussenbaum B, Rees RS, Schwartz J, Johnson TM, Bradford CR. Reliability of sentinel lymph node mapping with biopsy for head and neck cutaneous melanoma. Arch Otolaryngol Head Neck Surg 2003;129:61–65. 11. Erman AB, Collar RM, Griffith KA, et al. Sentinel lymph node biopsy is accurate and prognostic in head and neck melanoma. Cancer 2012;118: 1040–1047. 12. Saltman BE, Ganly I, Patel SG, et al. Prognostic implication of sentinel lymph node biopsy in cutaneous head and neck melanoma. Head Neck 2010;32:1686–1692. 13. Faries MB, Wanek LA, Elashoff D, Wright BE, Morton DL. Predictors of occult nodal metastasis in patients with thin melanoma. Arch Surg 2010; 145:137–142. 14. Karakousis CP, Balch CM, Urist MM, Ross MM, Smith TJ, Bartolucci AA. Local recurrence in malignant melanoma: long-term results of the multiinstitutional randomized surgical trial. Ann Surg Oncol 1996;3:446–452. 15. Lachiewicz AM, Berwick M, Wiggins CL, Thomas NE. Survival differences between patients with scalp or neck melanoma and those with melanoma of other sites in the Surveillance, Epidemiology, and End Results (SEER) program. Arch Dermatol 2008;144:515–521. 16. Larson DL, Larson JD. Head and neck melanoma. Clin Plast Surg 2010;37: 73–77. 17. Tseng WH, Martinez SR. Tumor location predicts survival in cutaneous head and neck melanoma. J Surg Res 2011;167:192–198. 18. Pathak I, O’Brien CJ, Petersen–Schaeffer K, et al. Do nodal metastases from cutaneous melanoma of the head and neck follow a clinically predictable pattern? Head Neck 2001;23:785–790.
HEAD & NECK—DOI 10.1002/HED
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