- Email: [email protected]
The role of sentinel lymph node biopsy in patients with thick melanoma. A single centre experience
t h e s u r g e o n 1 0 ( 2 0 1 2 ) 6 5 e7 0
available at www.sciencedirect.com
The Surgeon, Journal of the Royal Colleges of Surgeons of Edinburgh and Ireland www.thesurgeon.net
The role of sentinel lymph node biopsy in patients with thick melanoma. A single centre experience J. Kelly*, H.P. Redmond Department of Academic Surgery, Cork University Hospital, Cork, Ireland
article info
abstract
Article history:
Aims: To evaluate the role, if any, of sentinel lymph node mapping (SLNM) with biopsy
Received 5 August 2010
(SLNB) in patients with thick cutaneous melanoma.
Received in revised form
Methods: Consecutive patients with thick (Breslow 4 mm) cutaneous melanoma, under-
26 January 2011
going SLNB were identified from a departmental database comprising 550 patients in total
Accepted 29 January 2011
from 2000 to 2010. Factors examined included demographic data, histological subtype, site
Available online 3 March 2011
and depth of lesion, percentage of positive SLNs, regional recurrence in the setting of a negative SLNB result (false-negative rate), complications, further lymphadenectomy, and
Keywords:
follow-up (disease free and overall survival), where available.
Thick melanoma
Results: Sixty-four eligible patients (37 men, 27 women) underwent primary excision and
Breslow
SLNM. Median patient age was 59 years (range 8e82 years). Mean Breslow depth was 7 mm
Sentinel lymph node biopsy
(range 4e19 mm). Thirty melanomas were located on the limbs, 19 on the head and neck and 15 on the trunk. Twenty-three (35%) were ulcerated. Of the 57 patients who had a sentinel node identified, 18 (31%) had metastatic melanoma identified. The mean survival time for patients with a negative SLN was 79 months versus 18 months for those with a positive node. Patients with a negative SLN have a 5 year disease free survival of 79% versus 11% ( p < 0.001) and an overall 5 year survival rate of 85% versus 32% when compared to node positive patients. Conclusions: The status of the SLN is predictive of disease recurrence and overall survival in patients with a thick primary cutaneous melanoma. This modality should be employed, where applicable, in this cohort of patients. ª 2011 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.
Introduction The status of the regional lymph node basin has been shown to be the most important prognostic indicator for patients diagnosed with cutaneous melanoma. Melanomas less than 1 mm rarely metastasise while at least 25% of melanomas between 1.5 and 4.0 mm and greater than 60% of melanomas greater than 4.0 mm thick will have lymph node metastases at
presentation.1 The outcome from melanoma also depends heavily on the stage at presentation. Patients with early stage disease (i.e. < 1 mm thick) achieve long-term survival in more than 90% of cases. For patients with melanomas greater than 1.0 mm thickness, survival rates range from 50% to 90%.2 The introduction of the SLNB technique for the evaluation of patients with truncal and extremity melanoma showed that the status of the SLN accurately represented the status of the
* Corresponding author. Tel.: þ353214922371. E-mail address: [email protected] (J. Kelly). 1479-666X/$ e see front matter ª 2011 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.surge.2011.01.012
66
t h e s u r g e o n 1 0 ( 2 0 1 2 ) 6 5 e7 0
entire nodal basin from which it was obtained. This study highlighted a novel technique of identifying patients with occult nodal metastasis who warranted therapeutic lymphadenectomy and possible adjuvant therapy, whilst also sparing the remaining 80% of patients without regional disease the morbidity associated with a formal lymphadenectomy procedure.3 The preliminary findings of the MSLT-1 trial (Multicentre Selective Lymphadenectomy Trial) represent the first randomised prospective clinical study to show a potential survival advantage to performing sentinel lymph node biopsy in patients with melanoma.4 However, this study was limited to lesions between 1 and 4 mm in thickness. Thus, no firm data exist about the applications of this proven staging method to patients with melanomatous lesions <1 mm or 4 mm in thickness. Specifically, for patients with intermediate thickness (1.2e3.5 mm) primary melanomas, there was no significant difference in overall melanoma-related survival but did show improved disease free survival in those patients who underwent the SLNB compared to those in the nodal observation arm group; thus there was a 26% reduction in the relative risk of recurrence (hazard ration 0.74; 95% confidence interval 0.59e0.93; p ¼ 0.009) which was durable for at least 10 years.4 The prognosis of patients with a thick melanoma (Breslow thickness 4 mm) is poor, with a 10-year melanoma specific mortality rate >50%2 and 5-year disease free survival of <50%,6 causing both treatment difficulty and uncertainty for doctors, as well as patients. Because of the poor prognosis, high degree of synchronous metastatic disease at initial presentation and further systemic disease in patients with a thick primary melanoma,7 the approach to the regional lymph nodes remains controversial.8,9 The high risk of synchronous distant metastases is suggested by some to outweigh any benefit of staging or the possible therapeutic benefit of elective lymph node dissection in this group of patients.10 However, a significant amount of these patients survive without recurrent disease. Detection of lymph node involvement in thick melanomas may help to identify this group, particularly given that other factors (ulceration and Clark level) seem to have less prognostic value in this group of melanoma patients.11,12 The proven benefits for performing SLNB at the time of oncological wide local excision of a primary melanoma include both prognostic and staging information, the potential therapeutic impact of a completion lymph node dissection in those with a positive SLN. Finally and most importantly in this cohort of patients, the status of the sentinel node has direct and future implications for the patient when being considered for adjuvant therapy decisions or entry into pertinent clinical trials. Heretofore, numerous trials investigating the potential use of myriad adjuvant therapies including vaccines, differing combinations of chemotherapeutic agents, immunostimulants, cytokines and growth factors have failed to show any efficacy to date in terms of overall survival benefit.13,14 The only adjuvant agent currently approved for use is interferon alpha (IFN-a). A recent study by Mocellin examining 14 randomised controlled trials, between 1990 and 2008 involving 8122 patients showed statistically significant improvement in both disease free (risk reduction ¼ 18%) and overall survival
(risk reduction ¼ 11%) for high risk patients treated with IFNa compared to observation alone or versus a comparator.15 The recent development of vaccines that include agonists of various immune signalling like the MAGE-3 ASCI has also revived the field of cancer vaccines.16 One patient treated in our own institution has recently been enrolled into the DERMA trial (adjuvant immunotherapy with MAGE-A3 in melanoma). Furthermore, there is growing concern surrounding the reliability of the SLN to accurately predict the disease status of the entire nodal basin. Specific problems have been identified in the head and neck region where the complexity and variability of the interlacing network of cervical lymphatics has been and showed a 34% discordance rate between the clinical prediction of lymphatic drainage and lymphoscintigraphy.17 The aim of this study was to evaluate the role, if any, of sentinel lymph node mapping with biopsy in patients with thick (Breslow 4 mm) cutaneous melanoma, by assessing the incidence of positive sentinel nodes and its subsequent prognostic value.
Materials and methods Patients Consecutive patients with primary cutaneous melanoma undergoing SLNM with biopsy in our institution were evaluated. This subgroup of patients was identified from a prospectively maintained departmental database comprising 550 patients in total from 2000e2010. To ensure patient confidentiality, access to this database was limited to one person (JK). Factors examined included demographic data, histological subtype, site and depth of lesion, peri-operative lymphoscintigraphy, percentage of positive SLNs, regional recurrence in the setting of a negative SLNB result (falsenegative rate), complications, further lymphadenectomy and follow-up (disease free survival and overall survival data), where available. The SLNB technique performed adhered to internationally recognised guidelines.18 Before SLNB was performed, a routine chest X-ray was performed to rule out obvious pulmonary metastases and only patients with clinically localized disease received SLNB for nodal staging.
Node identification All patients underwent preoperative lymphoscintigraphy to ascertain the number and location of regional nodal basins at risk for metastatic disease. The lymphoscintigraphy was performed in the Department of Nuclear Medicine the morning of the patients’ surgery using a standard dose of technetium (37 MBq of 99mTc-nanocolloid) injected intradermally into the 4 quadrants surrounding the primary melanoma lesion. Planar and dynamic phase imagings were performed 2 h following injection. The SLN was then identified by a combination of the lymphoscintigraphy, intra-operative blue dye and peri-operative hand-held gamma probe (Navigator, USCC, USA). Infrequently, we do not use intraoperative blue dye particularly for melanomas affecting the
67
t h e s u r g e o n 1 0 ( 2 0 1 2 ) 6 5 e7 0
face for two reasons. We feel that injection of the blue dye itself around the lesion can lead to further aesthetic disturbance and that it also remains around the injection site for a considerable amount of time. We define a sentinel lymph node as a blue lymph node and/or a radioactive node, with an ex vivo/background activity ratio of 10 or more. The procedure was complete when all nodal basins had minimal background radioactivity relative to the primary lesion and sentinel nodes. SLNB was combined with, and performed before, wide local re-excision of the biopsy site of the primary tumour (excision margin of 2 cm for all cutaneous melanomas 4 mm in thickness), conforming to current recommendations.19
Histopathological examination All SLNs retrieved were sent for histological evaluation using serial permanent sectioning by the same 2 pathologists over the study period. Evaluation included staining with haematoxylineeosin (H&E). If the SLNs were negative with H&E staining, further evaluation was performed using immunohistochemical staining for S100, melan-A and HMB-45. A sentinel node was classified as a positive sentinel node if tumour cells were detected within the sentinel node. Patients who had a positive SLN result were offered further completion lymphadenectomy within 3 weeks of their SLNM procedure. All patients were followed-up as per Cork University Hospital Clinical Guidelines for Melanoma. No patients were lost to follow-up. Survival information was obtained, where available, from outpatient clinic visits documented in patients’ charts. Disease free survival (DFS) was calculated from the time of definitive surgery. Loco-regional recurrence was defined as any histopathologically confirmed local recurrence, in-transit recurrence, or regional recurrence within a primary draining lymph node basin.
Statistical analysis Disease free survival (DFS) was calculated for each patient beginning at the date of surgery. For DFS, patients were followed until date of documented distant disease or death. KaplaneMeier curves were constructed to analyze survival. Logrank tests were used to calculate significance in survival differences. Significance for all statistical tests was defined as a p value <0.05%.
Results Seventy eight patients (14%) with a thick (Breslow thickness 4 mm) cutaneous melanoma were identified from a prospectively maintained departmental melanoma database from 2000e2010 comprising 550 patients. Of these 78 patients, we excluded 14 from this study; 10 (13%) had distant metastases at presentation, 2 had previous surgery to the predicted draining lymph nodes and 2 patients that were deemed to be unfit for any further surgical intervention after wide local excision was completed due to significant medical co-morbidities. Thus 64 patients were enrolled in the study proper.
Table 1 e Histological features. Subtype
Total No.
Head & Neck
Trunk
Limbs
9 e 5 e
15 2 11 1 1
Nodular Superficial spreading Lentigo Spitz/Spindle Amelanotic Desmoid
37 19 3 3 1 1
13 1 3 2
Total Ulceration
64 23 (35%)
19 (30%) 3
1 15 (23%) 3
30 (47%) 17
Of the remaining 64 evaluable patients who underwent primary excision and SLNM, 37 (58%) were men and 27 (42%) were women. The median patient age was 59 years (range 8e82 years). The mean Breslow depth was 7 mm (range 4e19 mm). Melanoma subtypes included nodular 37 (58%), superficial spreading 19 (30%), lentigo 3, spindle cell/spitzoid 3, amelanotic and desmoid 1 of each. Thirty (47%) melanomas were located on the limbs, 19 (30%) on the head and neck and 15 (23%) on the trunk. Twenty-three (35%) of the lesions were ulcerated. The histological features are listed in Table 1. Using a combination of preoperative lymphoscintigraphy, intra-operative gamma probe and isosulfan blue dye, an SLN was found in 57/64 cases (89%) performed. The node was identified using the gamma probe in 48/57 cases and the remaining 9 cases were found with the further use of blue dye. The average number of lymph nodes retrieved per patient was 2 (range 1e5). Of the 57 patients, 18 (31%) had metastatic melanoma identified using SLNB (SLNþ). A further breakdown of these patients according to site of melanoma is shown in Table 2. All these patients underwent further lymphadenectomy. The SLN failed to map in 7/64 (11%) cases with relatively even distribution according to the primary site of the lesion (data not shown). Table 3 shows the pathological results of the subsequent lymphadenectomies performed on all patients who had a positive sentinel lymph node biopsy. Fifty percent of patients who had a positive sentinel lymph node biopsy had further regional lymph node metastatic disease. Recurrences were more frequent in patients with a positive SLN (n ¼ 16/18 or 88%) than in those with a negative SLN (n ¼ 8/ 39 or 20%). The mean survival time for patients with a negative SLN was 79 months versus 18 months for those with a positive SLN (log rank p < 0.001). In particular, patients with a negative SLN have a 5 year disease free survival of 79% versus 11% for those with a positive SLN (log rank p < 0.001); see Fig. 1. The
Table 2 e results of SLNM (sentinel lymph node mapping). Site of Melanoma
No
SLN Mapping
Failed SLNM
Positive SLN
Negative SLN
H&N Trunk Limb Total
19 15 30 64
16 13 28 57
3 2 2 7
3 4 11 18 (31%)
13 9 17 39 (68%)
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t h e s u r g e o n 1 0 ( 2 0 1 2 ) 6 5 e7 0
Table 3 e Analysis of subsequent lymphadenectomies Site of Positive Lymphadenectomy Further Positive Melanoma SLN (Cx/Ax/Ing) LN Disease H&N Trunk Limb
3 4 11
Total
18
3 4 9 2
Cx Ax Ing Ax
1/3 3/4 5/11 9/18 (50%)
Cx ¼ cervical, Ax ¼ axillary and Ing ¼ inguinal.
overall 5 year survival rate for those with a positive SLN was 32% compared to 85% of those with a negative SLN. The SLN failed to map in 7/64 (11%) cases of patients with thick melanoma. Of these, 2 patients developed metastatic disease. Both were males, with primary nodular melanoma of the trunk (one developed liver metastases at 24/12 and another local recurrence at 12/12).
Discussion The advantages of SLNB are numerous. It improves the accuracy of staging and provides valuable prognostic information to guide subsequent treatment decisions. It allows early therapeutic lymph node dissection for patients with nodal metastases and determines those who may benefit from adjuvant therapy with interferon a or those suitable to enter into clinical trials. Experts dealing with patients with melanoma from around the world recently agreed that the histopathological evaluation of the sentinel lymph node become the standard of care in current practise.5 There is also widespread agreement that the prognosis in terms of disease free and overall survival rates for patients with thick melanoma in specific is poor.2,6 Because of the poor prognosis, high degree of synchronous metastatic disease at initial presentation and further systemic disease in patients with a thick primary melanoma,7 the approach to the regional lymph nodes remains extremely controversial.8,9 This imbalance provides a distinct problem for both doctors and this cohort of patients.
Fig. 1 e KaplaneMeier survival curve of patients in this study. The 5 year DFS for SLN negative and SLN positive patients was 79% and 11% (log rank p < 0.001).
Fourteen percent of patients in our registry presented with a thick primary cutaneous melanoma. The mean Breslow depth was 7 mm, commonest histological subtype was nodular, 35% were ulcerated and occult metastatic disease was identified in 18/54 that underwent SLNM. Studies suggest that the risk of distant metastatic disease in patients with thick melanomas is high and that they have such a poor prognosis that subsequent treatment of the regional lymph node basin confers no therapeutic benefit.9 Furthermore, MSLT-1 or other prospective melanoma trial to date did not include any patients with thick primary melanomas. However, recent data have suggested that the above situation may not be as dramatic as initially thought, both in terms of
Table 4 e Published data on thick cutaneous melanoma Study Year No of patients Median age (years) Median follow-up (months) Mean tumour thickness (mm) % Ulceration present % of þ SLN 5 year DFS þ SLN SLN 5 year OS þ SLN SLN
Gershenwald12 Essner8 Thompson9 Ferrone21 Carlson22 Gutzmer24 Vermeeren28 Gajdos23 2000 126 57 36 5.0 50% 39%
2002 113 54 31 5.9 45% 35%
2002 172 61 24 5.0 (median) 53% 30%
2002 126 60 16 5.5 43% 30%
48% 64%
34% 47%
29% 68%
32% 56%
54% 87%
50% 60%
41% 74%
2003 114 57 34 6.3 35% 32.5% 3 years 31% 71%
2008 152 65 33 5.2 58% 48%
2009 31 59 44 6.8 (median) 62.5% 64.5%
26% 58%
40% 60%
57% 82%
37% 67%
42% 68%
SLN: sentinel lymph node; þ: positive; : negative; DFS: disease free survival and OS: overall survival.
2009 228 58 43 6.6 34% 47%
47% 80%
t h e s u r g e o n 1 0 ( 2 0 1 2 ) 6 5 e7 0
occult regional metastatic disease and subsequent prognosis for patients with thick non-ulcerated melanomas without evidence of regional lymph node involvement.8,9,11,12,20 A review of data currently available in the literature concerning other institutions’ experience with SLNB in thick cutaneous melanoma is presented in Table 4. Concerning the prognostic role for SLNB in patients with thick cutaneous primary melanoma, the overall message from these studies remains unclear. Gershenwald found that, even though both the presence of ulceration and SLN status were independent prognostic factors with respect to disease-free and overall survival, SLN status was the most powerful predictor of overall survival by univariate and multivariate analyses.12 Essner also found that the status of the SLN is predictive of 5 year disease free survival but not overall survival. This group found no difference between ulcerated and non-ulcerated lesions in terms of survival.8 Ferrone developed an interesting multivariate prognostic model for patients with thick cutaneous melanoma and found that the factors independently predictive of recurrence were age >60 years, depth >5.5 mm, ulceration, and SLN positivity, with the latter factor being the most significant prognosticator. The relative risk for an individual recurrence ranged from 1 in patients for whom no adverse factors were present to 29.4 when all factors were present. They concluded that these patients are prognostically heterogeneous, and all independently predictive factors should be considered when assessing an individual patient’s risk of recurrence.21 Our study shows that patients with a thick primary cutaneous melanoma with metastatic deposit in their regional lymph node basin have a poorer prognosis in terms of disease free and overall survival. In experienced hands, the SLN can be identified in nearly 100% of cases, with a false-negative rate of <5% and little morbidity.18,25 Regional nodal failures in all melanoma patients following a negative SLNB are uncommon and some studies have previously suggested that this was most commonly because conventional histological evaluation was unable to identify occult metastatic disease.26 The SLN failed to map in 7/64 (11%) cases of our patients with thick melanoma. Various reasons have been suggested as to why SLNM fails. These include (1) when the primary lesion is overlying the draining lymph node basin, (2) learning curve of the performing surgeon/pathologist/nuclear medicine staff, (3) inappropriately high radioactivity level, (4) movement of the dye into the second or non-sentinel lymph node and (5) incorrect injection technique of the dye. It has been suggested that a 30 person learning curve be recommended for a surgeon performing these cases.18 The performing surgeon in this study carried out all surgical procedures and has successfully identified the sentinel node in >400 patients with cutaneous melanoma. Experienced nuclear medicine staff is imperative as inappropriate administration of the radiolabelled isotope can directly affect the outcome of the procedure. Interpretation by a pathologist experienced in the technique of SLNB is imperative as a more thorough and detailed analysis of the SLNs is required than when examining a formal lymphadenectomy sample.27 It is also important to accurately select patients who are suitable to undergo SLNB. We excluded patients with stage
69
III/IV disease, patients who had previous surgery to the predicted draining lymphatic tissue and those patients that were deemed to be unfit for any further surgical intervention after wide local excision was completed due to significant medical co-morbidities.
Conclusions This study shows that the status of the SLN is predictive of disease recurrence and overall survival in patients with a thick primary cutaneous melanoma. Justifiably, this method should be employed, where applicable, in this cohort of patients.
Conflict of interest None.
references
1. Pacifico MD, Grover R, Sanders R. Use of an early-detection strategy to improve disease control in melanoma patients. Br J Plast Surg 2004;57(2):105e11. 2. Balch CM, Buzaid AC, Soong SJ, Atkins MB, Cascinelli N, Coit DG, et al. Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on cancer melanoma staging system. J Clin Oncol 2001;19(16): 3622e34. 3. Morton DL, Wen DR, Wong JH, Economou JS, Cagle LA, Storm FK, et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 1992;127(4): 392e9. 4. Morton DL, Thompson JF, Cochran AJ, Mozzillo N, Elashoff R, Essner R, et al. Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med 2006;355(13):1307e17. 5. Balch CM, Morton DL, Gershenwald JE, McMasters KM, Nieweg OE, Powell B, et al. Sentinel node biopsy and standard of care for melanoma. J Am Acad Dermatol 2009;60(5):872e5. 6. Salti GI, Kansagra A, Warso MA, Ronan SG, Das Gupta TK. Clinical node-negative thick melanoma. Arch Surg 2002; 137(3):291e5. 7. Reintgen D, Balch CM, Kirkwood J, Ross M. Recent advances in the care of the patient with malignant melanoma. Ann Surg 1997;225(1):1e14. 8. Essner R, Chung MH, Bleicher R, Hsueh E, Wanek L, Morton DL. Prognostic implications of thick (>or ¼ 4-mm) melanoma in the era of intraoperative lymphatic mapping and sentinel lymphadenectomy. Ann Surg Oncol 2002;9(8): 754e61. 9. Thompson JF, Shaw HM. The prognosis of patients with thick primary melanomas: is regional lymph node status relevant, and does removing positive regional nodes influence outcome? Ann Surg Oncol 2002;9(8):719e22. 10. Crowley NJ, Seigler HF. The role of elective lymph node dissection in the management of patients with thick cutaneous melanoma. Cancer 1990;66(12):2522e7. 11. Cherpelis BS, Haddad F, Messina J, Cantor AB, Fitzmorris K, Reintgen DS, et al. Sentinel lymph node micrometastasis and other histologic factors that predict outcome in patients with thicker melanomas. J Am Acad Dermatol 2001;44(5):762e6.
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12. Gershenwald JE, Mansfield PF, Lee JE, Ross MI. Role for lymphatic mapping and sentinel lymph node biopsy in patients with thick (> or ¼ 4 mm) primary melanoma. Ann Surg Oncol 2000;7(2):160e5. 13. Eggermont AM, Gore M. Randomized adjuvant therapy trials in melanoma: surgical and systemic. Semin Oncol 2007;34(6): 509e15. 14. Spitler LE. Noninterferon-based adjuvant therapy for highrisk melanoma. Expert Rev Anticancer Ther 2002;2(5):547e62. 15. Mocellin S, Pasquali S, Rossi CR, Nitti D. Interferon alpha adjuvant therapy in patients with high-risk melanoma: a systematic review and meta-analysis. J Natl Cancer Inst 2010; 102(7):493e501. 16. Weber J. Immunotherapy for melanoma. Curr Opin Oncol 2011; 23(2):163e9. 17. O’Brien CJ, Uren RF, Thompson JF, Howman-Giles RB, Petersen-Schaefer K, Shaw HM, et al. Prediction of potential metastatic sites in cutaneous head and neck melanoma using lymphoscintigraphy. Am J Surg 1995;170(5):461e6. 18. Morton DL, Thompson JF, Essner R, Elashoff R, Stern SL, Nieweg OE, et al. Validation of the accuracy of intraoperative lymphatic mapping and sentinel lymphadenectomy for earlystage melanoma: a multicenter trial. Multicenter selective lymphadenectomy trial group. Ann Surg 1999;230(4):453e63. Discussion 463e5. 19. Thomas JM, Newton-Bishop J, A’Hern R, Coombes G, Timmons M, Evans J, et al. Excision margins in high-risk malignant melanoma. N Engl J Med 2004;350(8):757e66. 20. Kim SH, Garcia C, Rodriguez J, Coit DG. Prognosis of thick cutaneous melanoma. J Am Coll Surg 1999;188(3):241e7.
21. Ferrone CR, Panageas KS, Busam K, Brady M, Coit DG. Multivariate prognostic model for patients with thick cutaneous melanoma: importance of sentinel lymph node status. Ann Surg Oncol 2002;9(7):637e45. 22. Carlson GW, Murray DR, Hestley A, Staley CA, Lyles RH, Cohen C. Sentinel lymph node mapping for thick (>or ¼ 4mm) melanoma: should we be doing it? Ann Surg Oncol 2003; 10(4):408e15. 23. Gajdos C, Griffith KA, Wong SL, Johnson TM, Chang AE, Cimmino VM, et al. Is there a benefit to sentinel lymph node biopsy in patients with T4 melanoma? Cancer 2009;115(24): 5752e60. 24. Gutzmer R, Satzger I, Thoms KM, Volker B, Mitteldorf C, Kapp A, et al. Sentinel lymph node status is the most important prognostic factor for thick (> or ¼ 4 mm) melanomas. J Dtsch Dermatol Ges 2008;6(3):198e203. 25. Wrightson WR, Wong SL, Edwards MJ, Chao C, Reintgen DS, Ross MI, et al. Complications associated with sentinel lymph node biopsy for melanoma. Ann Surg Oncol 2003;10(6):676e80. 26. Gershenwald JE, Colome MI, Lee JE, Mansfield PF, Tseng C, Lee JJ, et al. Patterns of recurrence following a negative sentinel lymph node biopsy in 243 patients with stage I or II melanoma. J Clin Oncol 1998;16(6):2253e60. 27. Cascinelli N, Belli F, Santinami M, Fait V, Testori A, Ruka W, et al. Sentinel lymph node biopsy in cutaneous melanoma: the WHO melanoma program experience. Ann Surg Oncol 2000;7(6):469e74. 28. Vermeeren L, van der Ent FW, Sastrowijoto PS, Hulsewe KW. Thick melanoma: prognostic value of positive sentinel nodes. World J Surg 2009;33(11):2464e8.
available at www.sciencedirect.com
The Surgeon, Journal of the Royal Colleges of Surgeons of Edinburgh and Ireland www.thesurgeon.net
The role of sentinel lymph node biopsy in patients with thick melanoma. A single centre experience J. Kelly*, H.P. Redmond Department of Academic Surgery, Cork University Hospital, Cork, Ireland
article info
abstract
Article history:
Aims: To evaluate the role, if any, of sentinel lymph node mapping (SLNM) with biopsy
Received 5 August 2010
(SLNB) in patients with thick cutaneous melanoma.
Received in revised form
Methods: Consecutive patients with thick (Breslow 4 mm) cutaneous melanoma, under-
26 January 2011
going SLNB were identified from a departmental database comprising 550 patients in total
Accepted 29 January 2011
from 2000 to 2010. Factors examined included demographic data, histological subtype, site
Available online 3 March 2011
and depth of lesion, percentage of positive SLNs, regional recurrence in the setting of a negative SLNB result (false-negative rate), complications, further lymphadenectomy, and
Keywords:
follow-up (disease free and overall survival), where available.
Thick melanoma
Results: Sixty-four eligible patients (37 men, 27 women) underwent primary excision and
Breslow
SLNM. Median patient age was 59 years (range 8e82 years). Mean Breslow depth was 7 mm
Sentinel lymph node biopsy
(range 4e19 mm). Thirty melanomas were located on the limbs, 19 on the head and neck and 15 on the trunk. Twenty-three (35%) were ulcerated. Of the 57 patients who had a sentinel node identified, 18 (31%) had metastatic melanoma identified. The mean survival time for patients with a negative SLN was 79 months versus 18 months for those with a positive node. Patients with a negative SLN have a 5 year disease free survival of 79% versus 11% ( p < 0.001) and an overall 5 year survival rate of 85% versus 32% when compared to node positive patients. Conclusions: The status of the SLN is predictive of disease recurrence and overall survival in patients with a thick primary cutaneous melanoma. This modality should be employed, where applicable, in this cohort of patients. ª 2011 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.
Introduction The status of the regional lymph node basin has been shown to be the most important prognostic indicator for patients diagnosed with cutaneous melanoma. Melanomas less than 1 mm rarely metastasise while at least 25% of melanomas between 1.5 and 4.0 mm and greater than 60% of melanomas greater than 4.0 mm thick will have lymph node metastases at
presentation.1 The outcome from melanoma also depends heavily on the stage at presentation. Patients with early stage disease (i.e. < 1 mm thick) achieve long-term survival in more than 90% of cases. For patients with melanomas greater than 1.0 mm thickness, survival rates range from 50% to 90%.2 The introduction of the SLNB technique for the evaluation of patients with truncal and extremity melanoma showed that the status of the SLN accurately represented the status of the
* Corresponding author. Tel.: þ353214922371. E-mail address: [email protected] (J. Kelly). 1479-666X/$ e see front matter ª 2011 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.surge.2011.01.012
66
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entire nodal basin from which it was obtained. This study highlighted a novel technique of identifying patients with occult nodal metastasis who warranted therapeutic lymphadenectomy and possible adjuvant therapy, whilst also sparing the remaining 80% of patients without regional disease the morbidity associated with a formal lymphadenectomy procedure.3 The preliminary findings of the MSLT-1 trial (Multicentre Selective Lymphadenectomy Trial) represent the first randomised prospective clinical study to show a potential survival advantage to performing sentinel lymph node biopsy in patients with melanoma.4 However, this study was limited to lesions between 1 and 4 mm in thickness. Thus, no firm data exist about the applications of this proven staging method to patients with melanomatous lesions <1 mm or 4 mm in thickness. Specifically, for patients with intermediate thickness (1.2e3.5 mm) primary melanomas, there was no significant difference in overall melanoma-related survival but did show improved disease free survival in those patients who underwent the SLNB compared to those in the nodal observation arm group; thus there was a 26% reduction in the relative risk of recurrence (hazard ration 0.74; 95% confidence interval 0.59e0.93; p ¼ 0.009) which was durable for at least 10 years.4 The prognosis of patients with a thick melanoma (Breslow thickness 4 mm) is poor, with a 10-year melanoma specific mortality rate >50%2 and 5-year disease free survival of <50%,6 causing both treatment difficulty and uncertainty for doctors, as well as patients. Because of the poor prognosis, high degree of synchronous metastatic disease at initial presentation and further systemic disease in patients with a thick primary melanoma,7 the approach to the regional lymph nodes remains controversial.8,9 The high risk of synchronous distant metastases is suggested by some to outweigh any benefit of staging or the possible therapeutic benefit of elective lymph node dissection in this group of patients.10 However, a significant amount of these patients survive without recurrent disease. Detection of lymph node involvement in thick melanomas may help to identify this group, particularly given that other factors (ulceration and Clark level) seem to have less prognostic value in this group of melanoma patients.11,12 The proven benefits for performing SLNB at the time of oncological wide local excision of a primary melanoma include both prognostic and staging information, the potential therapeutic impact of a completion lymph node dissection in those with a positive SLN. Finally and most importantly in this cohort of patients, the status of the sentinel node has direct and future implications for the patient when being considered for adjuvant therapy decisions or entry into pertinent clinical trials. Heretofore, numerous trials investigating the potential use of myriad adjuvant therapies including vaccines, differing combinations of chemotherapeutic agents, immunostimulants, cytokines and growth factors have failed to show any efficacy to date in terms of overall survival benefit.13,14 The only adjuvant agent currently approved for use is interferon alpha (IFN-a). A recent study by Mocellin examining 14 randomised controlled trials, between 1990 and 2008 involving 8122 patients showed statistically significant improvement in both disease free (risk reduction ¼ 18%) and overall survival
(risk reduction ¼ 11%) for high risk patients treated with IFNa compared to observation alone or versus a comparator.15 The recent development of vaccines that include agonists of various immune signalling like the MAGE-3 ASCI has also revived the field of cancer vaccines.16 One patient treated in our own institution has recently been enrolled into the DERMA trial (adjuvant immunotherapy with MAGE-A3 in melanoma). Furthermore, there is growing concern surrounding the reliability of the SLN to accurately predict the disease status of the entire nodal basin. Specific problems have been identified in the head and neck region where the complexity and variability of the interlacing network of cervical lymphatics has been and showed a 34% discordance rate between the clinical prediction of lymphatic drainage and lymphoscintigraphy.17 The aim of this study was to evaluate the role, if any, of sentinel lymph node mapping with biopsy in patients with thick (Breslow 4 mm) cutaneous melanoma, by assessing the incidence of positive sentinel nodes and its subsequent prognostic value.
Materials and methods Patients Consecutive patients with primary cutaneous melanoma undergoing SLNM with biopsy in our institution were evaluated. This subgroup of patients was identified from a prospectively maintained departmental database comprising 550 patients in total from 2000e2010. To ensure patient confidentiality, access to this database was limited to one person (JK). Factors examined included demographic data, histological subtype, site and depth of lesion, peri-operative lymphoscintigraphy, percentage of positive SLNs, regional recurrence in the setting of a negative SLNB result (falsenegative rate), complications, further lymphadenectomy and follow-up (disease free survival and overall survival data), where available. The SLNB technique performed adhered to internationally recognised guidelines.18 Before SLNB was performed, a routine chest X-ray was performed to rule out obvious pulmonary metastases and only patients with clinically localized disease received SLNB for nodal staging.
Node identification All patients underwent preoperative lymphoscintigraphy to ascertain the number and location of regional nodal basins at risk for metastatic disease. The lymphoscintigraphy was performed in the Department of Nuclear Medicine the morning of the patients’ surgery using a standard dose of technetium (37 MBq of 99mTc-nanocolloid) injected intradermally into the 4 quadrants surrounding the primary melanoma lesion. Planar and dynamic phase imagings were performed 2 h following injection. The SLN was then identified by a combination of the lymphoscintigraphy, intra-operative blue dye and peri-operative hand-held gamma probe (Navigator, USCC, USA). Infrequently, we do not use intraoperative blue dye particularly for melanomas affecting the
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face for two reasons. We feel that injection of the blue dye itself around the lesion can lead to further aesthetic disturbance and that it also remains around the injection site for a considerable amount of time. We define a sentinel lymph node as a blue lymph node and/or a radioactive node, with an ex vivo/background activity ratio of 10 or more. The procedure was complete when all nodal basins had minimal background radioactivity relative to the primary lesion and sentinel nodes. SLNB was combined with, and performed before, wide local re-excision of the biopsy site of the primary tumour (excision margin of 2 cm for all cutaneous melanomas 4 mm in thickness), conforming to current recommendations.19
Histopathological examination All SLNs retrieved were sent for histological evaluation using serial permanent sectioning by the same 2 pathologists over the study period. Evaluation included staining with haematoxylineeosin (H&E). If the SLNs were negative with H&E staining, further evaluation was performed using immunohistochemical staining for S100, melan-A and HMB-45. A sentinel node was classified as a positive sentinel node if tumour cells were detected within the sentinel node. Patients who had a positive SLN result were offered further completion lymphadenectomy within 3 weeks of their SLNM procedure. All patients were followed-up as per Cork University Hospital Clinical Guidelines for Melanoma. No patients were lost to follow-up. Survival information was obtained, where available, from outpatient clinic visits documented in patients’ charts. Disease free survival (DFS) was calculated from the time of definitive surgery. Loco-regional recurrence was defined as any histopathologically confirmed local recurrence, in-transit recurrence, or regional recurrence within a primary draining lymph node basin.
Statistical analysis Disease free survival (DFS) was calculated for each patient beginning at the date of surgery. For DFS, patients were followed until date of documented distant disease or death. KaplaneMeier curves were constructed to analyze survival. Logrank tests were used to calculate significance in survival differences. Significance for all statistical tests was defined as a p value <0.05%.
Results Seventy eight patients (14%) with a thick (Breslow thickness 4 mm) cutaneous melanoma were identified from a prospectively maintained departmental melanoma database from 2000e2010 comprising 550 patients. Of these 78 patients, we excluded 14 from this study; 10 (13%) had distant metastases at presentation, 2 had previous surgery to the predicted draining lymph nodes and 2 patients that were deemed to be unfit for any further surgical intervention after wide local excision was completed due to significant medical co-morbidities. Thus 64 patients were enrolled in the study proper.
Table 1 e Histological features. Subtype
Total No.
Head & Neck
Trunk
Limbs
9 e 5 e
15 2 11 1 1
Nodular Superficial spreading Lentigo Spitz/Spindle Amelanotic Desmoid
37 19 3 3 1 1
13 1 3 2
Total Ulceration
64 23 (35%)
19 (30%) 3
1 15 (23%) 3
30 (47%) 17
Of the remaining 64 evaluable patients who underwent primary excision and SLNM, 37 (58%) were men and 27 (42%) were women. The median patient age was 59 years (range 8e82 years). The mean Breslow depth was 7 mm (range 4e19 mm). Melanoma subtypes included nodular 37 (58%), superficial spreading 19 (30%), lentigo 3, spindle cell/spitzoid 3, amelanotic and desmoid 1 of each. Thirty (47%) melanomas were located on the limbs, 19 (30%) on the head and neck and 15 (23%) on the trunk. Twenty-three (35%) of the lesions were ulcerated. The histological features are listed in Table 1. Using a combination of preoperative lymphoscintigraphy, intra-operative gamma probe and isosulfan blue dye, an SLN was found in 57/64 cases (89%) performed. The node was identified using the gamma probe in 48/57 cases and the remaining 9 cases were found with the further use of blue dye. The average number of lymph nodes retrieved per patient was 2 (range 1e5). Of the 57 patients, 18 (31%) had metastatic melanoma identified using SLNB (SLNþ). A further breakdown of these patients according to site of melanoma is shown in Table 2. All these patients underwent further lymphadenectomy. The SLN failed to map in 7/64 (11%) cases with relatively even distribution according to the primary site of the lesion (data not shown). Table 3 shows the pathological results of the subsequent lymphadenectomies performed on all patients who had a positive sentinel lymph node biopsy. Fifty percent of patients who had a positive sentinel lymph node biopsy had further regional lymph node metastatic disease. Recurrences were more frequent in patients with a positive SLN (n ¼ 16/18 or 88%) than in those with a negative SLN (n ¼ 8/ 39 or 20%). The mean survival time for patients with a negative SLN was 79 months versus 18 months for those with a positive SLN (log rank p < 0.001). In particular, patients with a negative SLN have a 5 year disease free survival of 79% versus 11% for those with a positive SLN (log rank p < 0.001); see Fig. 1. The
Table 2 e results of SLNM (sentinel lymph node mapping). Site of Melanoma
No
SLN Mapping
Failed SLNM
Positive SLN
Negative SLN
H&N Trunk Limb Total
19 15 30 64
16 13 28 57
3 2 2 7
3 4 11 18 (31%)
13 9 17 39 (68%)
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Table 3 e Analysis of subsequent lymphadenectomies Site of Positive Lymphadenectomy Further Positive Melanoma SLN (Cx/Ax/Ing) LN Disease H&N Trunk Limb
3 4 11
Total
18
3 4 9 2
Cx Ax Ing Ax
1/3 3/4 5/11 9/18 (50%)
Cx ¼ cervical, Ax ¼ axillary and Ing ¼ inguinal.
overall 5 year survival rate for those with a positive SLN was 32% compared to 85% of those with a negative SLN. The SLN failed to map in 7/64 (11%) cases of patients with thick melanoma. Of these, 2 patients developed metastatic disease. Both were males, with primary nodular melanoma of the trunk (one developed liver metastases at 24/12 and another local recurrence at 12/12).
Discussion The advantages of SLNB are numerous. It improves the accuracy of staging and provides valuable prognostic information to guide subsequent treatment decisions. It allows early therapeutic lymph node dissection for patients with nodal metastases and determines those who may benefit from adjuvant therapy with interferon a or those suitable to enter into clinical trials. Experts dealing with patients with melanoma from around the world recently agreed that the histopathological evaluation of the sentinel lymph node become the standard of care in current practise.5 There is also widespread agreement that the prognosis in terms of disease free and overall survival rates for patients with thick melanoma in specific is poor.2,6 Because of the poor prognosis, high degree of synchronous metastatic disease at initial presentation and further systemic disease in patients with a thick primary melanoma,7 the approach to the regional lymph nodes remains extremely controversial.8,9 This imbalance provides a distinct problem for both doctors and this cohort of patients.
Fig. 1 e KaplaneMeier survival curve of patients in this study. The 5 year DFS for SLN negative and SLN positive patients was 79% and 11% (log rank p < 0.001).
Fourteen percent of patients in our registry presented with a thick primary cutaneous melanoma. The mean Breslow depth was 7 mm, commonest histological subtype was nodular, 35% were ulcerated and occult metastatic disease was identified in 18/54 that underwent SLNM. Studies suggest that the risk of distant metastatic disease in patients with thick melanomas is high and that they have such a poor prognosis that subsequent treatment of the regional lymph node basin confers no therapeutic benefit.9 Furthermore, MSLT-1 or other prospective melanoma trial to date did not include any patients with thick primary melanomas. However, recent data have suggested that the above situation may not be as dramatic as initially thought, both in terms of
Table 4 e Published data on thick cutaneous melanoma Study Year No of patients Median age (years) Median follow-up (months) Mean tumour thickness (mm) % Ulceration present % of þ SLN 5 year DFS þ SLN SLN 5 year OS þ SLN SLN
Gershenwald12 Essner8 Thompson9 Ferrone21 Carlson22 Gutzmer24 Vermeeren28 Gajdos23 2000 126 57 36 5.0 50% 39%
2002 113 54 31 5.9 45% 35%
2002 172 61 24 5.0 (median) 53% 30%
2002 126 60 16 5.5 43% 30%
48% 64%
34% 47%
29% 68%
32% 56%
54% 87%
50% 60%
41% 74%
2003 114 57 34 6.3 35% 32.5% 3 years 31% 71%
2008 152 65 33 5.2 58% 48%
2009 31 59 44 6.8 (median) 62.5% 64.5%
26% 58%
40% 60%
57% 82%
37% 67%
42% 68%
SLN: sentinel lymph node; þ: positive; : negative; DFS: disease free survival and OS: overall survival.
2009 228 58 43 6.6 34% 47%
47% 80%
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occult regional metastatic disease and subsequent prognosis for patients with thick non-ulcerated melanomas without evidence of regional lymph node involvement.8,9,11,12,20 A review of data currently available in the literature concerning other institutions’ experience with SLNB in thick cutaneous melanoma is presented in Table 4. Concerning the prognostic role for SLNB in patients with thick cutaneous primary melanoma, the overall message from these studies remains unclear. Gershenwald found that, even though both the presence of ulceration and SLN status were independent prognostic factors with respect to disease-free and overall survival, SLN status was the most powerful predictor of overall survival by univariate and multivariate analyses.12 Essner also found that the status of the SLN is predictive of 5 year disease free survival but not overall survival. This group found no difference between ulcerated and non-ulcerated lesions in terms of survival.8 Ferrone developed an interesting multivariate prognostic model for patients with thick cutaneous melanoma and found that the factors independently predictive of recurrence were age >60 years, depth >5.5 mm, ulceration, and SLN positivity, with the latter factor being the most significant prognosticator. The relative risk for an individual recurrence ranged from 1 in patients for whom no adverse factors were present to 29.4 when all factors were present. They concluded that these patients are prognostically heterogeneous, and all independently predictive factors should be considered when assessing an individual patient’s risk of recurrence.21 Our study shows that patients with a thick primary cutaneous melanoma with metastatic deposit in their regional lymph node basin have a poorer prognosis in terms of disease free and overall survival. In experienced hands, the SLN can be identified in nearly 100% of cases, with a false-negative rate of <5% and little morbidity.18,25 Regional nodal failures in all melanoma patients following a negative SLNB are uncommon and some studies have previously suggested that this was most commonly because conventional histological evaluation was unable to identify occult metastatic disease.26 The SLN failed to map in 7/64 (11%) cases of our patients with thick melanoma. Various reasons have been suggested as to why SLNM fails. These include (1) when the primary lesion is overlying the draining lymph node basin, (2) learning curve of the performing surgeon/pathologist/nuclear medicine staff, (3) inappropriately high radioactivity level, (4) movement of the dye into the second or non-sentinel lymph node and (5) incorrect injection technique of the dye. It has been suggested that a 30 person learning curve be recommended for a surgeon performing these cases.18 The performing surgeon in this study carried out all surgical procedures and has successfully identified the sentinel node in >400 patients with cutaneous melanoma. Experienced nuclear medicine staff is imperative as inappropriate administration of the radiolabelled isotope can directly affect the outcome of the procedure. Interpretation by a pathologist experienced in the technique of SLNB is imperative as a more thorough and detailed analysis of the SLNs is required than when examining a formal lymphadenectomy sample.27 It is also important to accurately select patients who are suitable to undergo SLNB. We excluded patients with stage
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III/IV disease, patients who had previous surgery to the predicted draining lymphatic tissue and those patients that were deemed to be unfit for any further surgical intervention after wide local excision was completed due to significant medical co-morbidities.
Conclusions This study shows that the status of the SLN is predictive of disease recurrence and overall survival in patients with a thick primary cutaneous melanoma. Justifiably, this method should be employed, where applicable, in this cohort of patients.
Conflict of interest None.
references
1. Pacifico MD, Grover R, Sanders R. Use of an early-detection strategy to improve disease control in melanoma patients. Br J Plast Surg 2004;57(2):105e11. 2. Balch CM, Buzaid AC, Soong SJ, Atkins MB, Cascinelli N, Coit DG, et al. Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on cancer melanoma staging system. J Clin Oncol 2001;19(16): 3622e34. 3. Morton DL, Wen DR, Wong JH, Economou JS, Cagle LA, Storm FK, et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 1992;127(4): 392e9. 4. Morton DL, Thompson JF, Cochran AJ, Mozzillo N, Elashoff R, Essner R, et al. Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med 2006;355(13):1307e17. 5. Balch CM, Morton DL, Gershenwald JE, McMasters KM, Nieweg OE, Powell B, et al. Sentinel node biopsy and standard of care for melanoma. J Am Acad Dermatol 2009;60(5):872e5. 6. Salti GI, Kansagra A, Warso MA, Ronan SG, Das Gupta TK. Clinical node-negative thick melanoma. Arch Surg 2002; 137(3):291e5. 7. Reintgen D, Balch CM, Kirkwood J, Ross M. Recent advances in the care of the patient with malignant melanoma. Ann Surg 1997;225(1):1e14. 8. Essner R, Chung MH, Bleicher R, Hsueh E, Wanek L, Morton DL. Prognostic implications of thick (>or ¼ 4-mm) melanoma in the era of intraoperative lymphatic mapping and sentinel lymphadenectomy. Ann Surg Oncol 2002;9(8): 754e61. 9. Thompson JF, Shaw HM. The prognosis of patients with thick primary melanomas: is regional lymph node status relevant, and does removing positive regional nodes influence outcome? Ann Surg Oncol 2002;9(8):719e22. 10. Crowley NJ, Seigler HF. The role of elective lymph node dissection in the management of patients with thick cutaneous melanoma. Cancer 1990;66(12):2522e7. 11. Cherpelis BS, Haddad F, Messina J, Cantor AB, Fitzmorris K, Reintgen DS, et al. Sentinel lymph node micrometastasis and other histologic factors that predict outcome in patients with thicker melanomas. J Am Acad Dermatol 2001;44(5):762e6.
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12. Gershenwald JE, Mansfield PF, Lee JE, Ross MI. Role for lymphatic mapping and sentinel lymph node biopsy in patients with thick (> or ¼ 4 mm) primary melanoma. Ann Surg Oncol 2000;7(2):160e5. 13. Eggermont AM, Gore M. Randomized adjuvant therapy trials in melanoma: surgical and systemic. Semin Oncol 2007;34(6): 509e15. 14. Spitler LE. Noninterferon-based adjuvant therapy for highrisk melanoma. Expert Rev Anticancer Ther 2002;2(5):547e62. 15. Mocellin S, Pasquali S, Rossi CR, Nitti D. Interferon alpha adjuvant therapy in patients with high-risk melanoma: a systematic review and meta-analysis. J Natl Cancer Inst 2010; 102(7):493e501. 16. Weber J. Immunotherapy for melanoma. Curr Opin Oncol 2011; 23(2):163e9. 17. O’Brien CJ, Uren RF, Thompson JF, Howman-Giles RB, Petersen-Schaefer K, Shaw HM, et al. Prediction of potential metastatic sites in cutaneous head and neck melanoma using lymphoscintigraphy. Am J Surg 1995;170(5):461e6. 18. Morton DL, Thompson JF, Essner R, Elashoff R, Stern SL, Nieweg OE, et al. Validation of the accuracy of intraoperative lymphatic mapping and sentinel lymphadenectomy for earlystage melanoma: a multicenter trial. Multicenter selective lymphadenectomy trial group. Ann Surg 1999;230(4):453e63. Discussion 463e5. 19. Thomas JM, Newton-Bishop J, A’Hern R, Coombes G, Timmons M, Evans J, et al. Excision margins in high-risk malignant melanoma. N Engl J Med 2004;350(8):757e66. 20. Kim SH, Garcia C, Rodriguez J, Coit DG. Prognosis of thick cutaneous melanoma. J Am Coll Surg 1999;188(3):241e7.
21. Ferrone CR, Panageas KS, Busam K, Brady M, Coit DG. Multivariate prognostic model for patients with thick cutaneous melanoma: importance of sentinel lymph node status. Ann Surg Oncol 2002;9(7):637e45. 22. Carlson GW, Murray DR, Hestley A, Staley CA, Lyles RH, Cohen C. Sentinel lymph node mapping for thick (>or ¼ 4mm) melanoma: should we be doing it? Ann Surg Oncol 2003; 10(4):408e15. 23. Gajdos C, Griffith KA, Wong SL, Johnson TM, Chang AE, Cimmino VM, et al. Is there a benefit to sentinel lymph node biopsy in patients with T4 melanoma? Cancer 2009;115(24): 5752e60. 24. Gutzmer R, Satzger I, Thoms KM, Volker B, Mitteldorf C, Kapp A, et al. Sentinel lymph node status is the most important prognostic factor for thick (> or ¼ 4 mm) melanomas. J Dtsch Dermatol Ges 2008;6(3):198e203. 25. Wrightson WR, Wong SL, Edwards MJ, Chao C, Reintgen DS, Ross MI, et al. Complications associated with sentinel lymph node biopsy for melanoma. Ann Surg Oncol 2003;10(6):676e80. 26. Gershenwald JE, Colome MI, Lee JE, Mansfield PF, Tseng C, Lee JJ, et al. Patterns of recurrence following a negative sentinel lymph node biopsy in 243 patients with stage I or II melanoma. J Clin Oncol 1998;16(6):2253e60. 27. Cascinelli N, Belli F, Santinami M, Fait V, Testori A, Ruka W, et al. Sentinel lymph node biopsy in cutaneous melanoma: the WHO melanoma program experience. Ann Surg Oncol 2000;7(6):469e74. 28. Vermeeren L, van der Ent FW, Sastrowijoto PS, Hulsewe KW. Thick melanoma: prognostic value of positive sentinel nodes. World J Surg 2009;33(11):2464e8.