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. Author manuscript; available in PMC: 2022 Dec 12.
Published in final edited form as: Ann Surg Oncol. 2017 May 15;24(9):2728–2733. doi: 10.1245/s10434-017-5883-6

Sentinel Lymph Node Biopsy for Recurrent Melanoma: A Multicenter Study

Georgia M Beasley 1, Yinin Hu 2, Linda Youngwirth 3, Randall P Scheri 3, April K Salama 4, Kara Rossfeld 1, Syed Gardezi 2, Doreen M Agnese 1, J Harrison Howard 1, Douglas S Tyler 5, Craig L Slingluff Jr 2, Alicia M Terando 1
PMCID: PMC9742856  NIHMSID: NIHMS1852390  PMID: 28508145

Abstract

Background.

Sentinel lymph node biopsy (SLNB) is routinely performed for primary cutaneous melanomas; however, limited data exist for SLNB after locally recurrent (LR) or in-transit (IT) melanoma.

Methods.

Data from three centers performing SLNB for LR/IT melanoma (1997 to the present) were reviewed, with the aim of assessing (1) success rate; (2) SLNB positivity; and (3) prognostic value of SLNB in this population.

Results.

The study cohort included 107 patients. Management of the primary melanoma included prior SLNB for 56 patients (52%), of whom 10 (18%) were positive and 12 had complete lymph node dissections (CLNDs). In the present study, SLNB was performed for IT disease (48/107, 45%) or LR melanoma (59/107, 55%). A sentinel lymph node (SLN) was removed in 96% (103/107) of cases. Nodes were not removed for four patients due to lymphoscintigraphy failures (2) or nodes not found during surgery (2). SLNB was positive in 41 patients (40%, 95% confidence interval (CI) 31.5-50.5), of whom 35 (88%) had CLND, with 13 (37%) having positive nonsentinel nodes. Median time to disease progression after LR/IT metastasis was 1.4 years (95% CI 0.75–2.0) for patients with a positive SLNB, and 5.9 years (95% CI 1.7–10.2) in SLNB-negative patients (p = 0.18). There was a trend towards improved overall survival for patients with a negative SLNB (p = 0.06).

Conclusion.

SLNB can be successful in patients with LR/IT melanoma, even if prior SLNB was performed. In this population, the rates of SLNB positivity and nonsentinel node metastases were 40% and 37%, respectively. SLNB may guide management and prognosis after LR/IT disease.

Sentinel lymph node biopsy (SLNB) has a well-established role in the management of primary cutaneous melanoma.1,2 The status of the sentinel lymph node (SLN) is the strongest prognostic factor in clinical stage I and II disease, and sentinel lymphadenectomy may provide therapeutic value.3,4 After appropriate initial surgical therapy of primary melanoma, 2–10% of extremity melanomas will recur locoregionally as satellite (S) metastases, in-transit (IT) disease, or locally recurrent (LR).5 Although current National Comprehensive Cancer Network guidelines recommend consideration of SLNB for S/IT/LR disease in the absence of extensive metastatic disease or clinical nodal involvement, the prognostic value of SLNB in this population is unclear.6 Furthermore, S/IT/LR metastases are considered American Joint Committee on Cancer (AJCC) 8th edition stage N1c (IIIB) without regional nodal involvement, stage N2c (IIIC) with one regional lymph node (LN) involved (IIIC), and N3c with two or more involved regional lymph nodes (IIIC), suggesting regional LN status possesses prognostic value within this population.7

A consideration not to perform SLNB in S/IT/LR disease is that systemic disease develops in approximately 50% of patients, for whom regional nodal failure is less of a concern.8 However, the status of the SLNB in S/IT/LR disease may help identify patients who could benefit from systemic therapy or lymphadenectomy. Retrospective data from two small series examining the role of SLNB for IT disease found the status of the SLN to be prognostic; SLN-positive patients had a median distant metastasis-free survival (MFS) of 19 months compared with 70 months for SLN-negative patients.9,10 These studies were limited by the small sample size (<60 each) and limited follow-up time, and they did not address implications for overall survival (OS).9–13 Additionally, the success rate of performing SLNB on S/IT/LR disease in patients with prior SLNB or LN dissections was not studied. The aims of this study were to (1) assess the feasibility of SLNB on LR/IT melanoma; (2) describe the rate of SLNB positivity; and (3) evaluate the prognostic value of SLNB in this population.

METHODS

Data from 1997 to the present were retrospectively collected from three institutions with Institutional Review Board (IRB) approval [Ohio State University IRB number 2016C0038 (n = 18 patients); University of Virginia IRB number 19590 (n = 56 patients); Duke University IRB number Pro00073199 (n = 33 patients)]. Patient data from Duke University (n = 33) were previously published, with applicable updates on disease recurrence or death.10

IT metastases were defined as lesions located more than 2 cm from the primary lesion but not beyond the regional nodal basin, while satellite lesions occur within 2 cm of the primary tumor. In the present study, 12 patients had recurrence of disease <60 days from the time of melanoma diagnosis, which was likely representative of residual primary disease. Therefore, in this study, we define local recurrence as lesions occurring within 2 cm of the primary tumor rather than designating these as satellite lesions. Patients with clinically evident regional nodal or distant metastatic disease were not considered for SLNB. In all three centers, standard clinical practice was to perform whole-body imaging to determine the absence of metastatic disease before SLNB.

The technical details of performing SLNB in this population have been previously described.10 All patients underwent lymphoscintigraphy using 0.5–1.0 mCi total technetium 99 m sulfur colloid in four to six equal aliquots around the tumor. When more than one IT lesion was present, the most proximal lesion was mapped, and when multiple lesions were present at the same level, the largest of the most proximal lesions was mapped. When resection of the LR/IT lesion was performed at the same time as SLNB, 1–3 ml of 1% isosulfan blue dye was injected around the lesion at Ohio State University and Duke University (n = 36). If resection of the lesions was not performed concurrently with SLNB, no blue dye was used (n = 15), and at the University of Virginia, no blue dye was used (n = 56).14 Similar guidelines were used for SLN removal of primary melanoma.15

IBM SPSS Statistics Software (IBM Corporation, Armonk, NY, USA) was used to carry out statistical analysis. Time to progression and time to death were compared between SLN-positive and SLN-negative patients using the log-rank test.

RESULTS

Overall, 107 patients underwent SLNB for LR (n = 59, 55%) or IT (n = 48, 45%) melanoma. The median time from initial melanoma diagnosis to LR/IT disease in 92 patients with data available was 24 months (range 38 days–16 years). The recurrence represented the first recurrence for 86% (92/107) of patients, while 56 patients (52%) underwent previous SLNB for the primary melanoma, 10 of whom had positive SLNBs (18%). Eight of 10 patients (80%) with a primary positive SLN underwent completion LN dissection (CLND). Two patients had prophylactic axillary LN dissections at the time of primary diagnosis, while two other patients had undergone prior hyperthermic isolated limb perfusions (HILP), a procedure that includes a pelvic lymph node dissection, for a total of 12 patients (11%) who had formal LN dissections prior to consideration of SLNB for the LR/IT recurrence.

SLNB was successfully completed in 96% (103/107) of cases overall. Lymphoscintigraphy from LR/IT melanoma was successful in identifying an SLN in 98% (105/107) of patients, while two patients, both with prior SLNBs, failed to have a node identified on lymphoscintigraphy and had resection of IT/LR disease only. Two other patients with recurrent back melanoma had nodes found on lymphoscintigraphy not found at surgery and had resection of IT/LR disease only. For the 46 patients who had undergone SLNB at the time of surgery for the primary melanoma, 24% (11/46) had an SLN removed from an additional basin at the time the LR/IT was mapped (Fig. 1a), while for the 12 patients who had prior LN dissections, 25% (3/12) had an SLN removed from an additional basin when the LR/IT was mapped (Fig. 1b). Removal of an SLN for LR/IT disease was successful in 96% (44/46) of patients with a prior SLNB, 83% (10/12) of patients with prior LN dissections, and 100% (51/51) of those without LN removal.

FIG. 1.

FIG. 1

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a Sites of sentinel lymph node in 46 patients at the time of primary melanoma (top) compared with site of sentinel node for IT or LR disease (bottom). b Sites of prior lymph node dissections in 12 patients at the time of primary melanoma (top) compared with site of sentinel node for IT or LR disease (bottom). SLNB sentinel lymph node biopsy, LR locally recurrent, IT in-transit

At surgery for LR/IT disease, 92/107 (86%) patients had resection of the LR/IT disease plus attempted SLNB (SLNB failures still had recurrent disease resected), while 15/107 (14%) patients had IT disease for which regional chemotherapy treatments were planned and had SLNB only. The rate of SLN positivity for all LR/IT disease was 40% (41/103, 95% CI 32–51%). SLN positivity was similar for LR disease (44%, 25/56) and IT disease (34%, 16/47). Eighty-five percent (35/41) of patients with a positive SLN underwent CLND. The reasons no completion was performed were development of systemic disease in 3/6 (50%) patients, and unclear in the remaining three patients. Of patients who underwent CLND, 37% (13/35) had nonsentinel node metastases. There appeared to be no difference in the rate of additional nodal metastases in those with LR disease (33%, 7/21) compared with those patients with IT disease (43%, 6/14). The median number of lymph nodes removed during groin dissections was 10 (n = 21), 26 (n = 11) for axillary dissections, and 20 (n = 3) for neck dissections.

At the time of primary melanoma, 56 patients underwent SLNB and 10 (18%) patients had a positive SLN (Table 1), of whom eight underwent CLND at that time. At the time of SNLB for LR/IT disease in those 10 patients, there were two failures to identify a sentinel node, both in patients with CLND. Excluding the failures, 6/8 (75%) patients who were SLN-positive at the time of primary disease were also SLN-positive at the time of LR/IT disease. For 46 patients who had a negative SLN at the time of primary disease, there were two failures to identify/remove an SLN at presentation with LR/IT disease. Excluding failures, 12/44 (27%) patients who were SLN negative at primary surgery had a positive SLN at surgery for LR/IT melanoma (Table 1).

TABLE 1.

SLNB status of IT/LR disease compared with SLNB at the time of primary melanoma

All patients LR/IT SLNB failure LR/IT SLNB positive (%) LR/IT SLNB negative (%)
Primary SLNB positive [n = 10] 2 6 of 8 (75) 2 of 8 (25)
Primary SLNB negative [n = 46] 2 12 of 44 (27) 32 of 44 (73)
No SLNB at primary [n = 51] 0 23 (45) 28 (55)
Total [n = 107] 4 41 (40) 62 (60)
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SLNB sentinel lymph node biopsy, LR locally recurrent, IT in-transit

Progression-free survival (PFS) and OS were calculated for all patients from the time of SLNB for LR/IT melanoma to disease progression, either locoregionally or systemically, or death for OS. There was a trend toward improved PFS for patients with LR/IT disease who were SLN-negative (median 6.0 years) versus SLN-positive (median 1.4 years), as shown in Fig. 2 (p = 0.176). There was also a trend for patients with LR/IT disease who were SLN-positive to have worse OS compared with those who were SLN-negative (5-year OS 61 vs. 78%, p = 0.06) [Fig. 3]. No differences were observed between the subgroups of LR SLN-positive versus SLN-negative or IT SLN-positive versus SLN-negative. However, there was a trend toward improved OS for patients with IT disease versus patients with LR disease (5-year OS 83 vs. 57%, p = 0.057) regardless of SLNB status.

FIG. 2.

FIG. 2

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Progression-free survival for patients with IT/LR disease and negative SLNB (blue) versus positive SLNB (yellow). SLNB sentinel lymph node biopsy, LN lymph node, LR locally recurrent, IT in-transit

FIG. 3.

FIG. 3

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Overall survival for patients with IT/LR disease and negative SLNB (blue) versus positive SLNB (yellow). Neg negative, Pos positive, SLNB sentinel lymph node biopsy, IT in-transit, LR locally recurrent

DISCUSSION

In the present study, SLNB for IT/LR melanoma was successful in 96% (44/46) of patients with a prior SLNB, 83% (10/12) of patients with prior LN dissections, and 100% (51/51) of patients with no history of LN removal. Furthermore, as expected from previous studies, the use of lymphoscintigraphy alone without blue dye for patients who were not undergoing concurrent excision of recurrent disease did not appear to affect the success rate of SLNB.14,16 Notably, the LR/IT sentinel node usually drained to the same regional basin as the original primary, although 24% (11/46) of cases had additional sites of LN drainage at the time of LR/IT.

The Multicenter Selective Lymphadenectomy (MSLT)-1 trial showed that the frequency of SLN positivity across all Breslow thicknesses was 20.8%.17,18 By comparison, the rate of SLN positivity with LR/IT in this study was 40% (41/103, 95% CI 31.5–50.5), emphasizing the difference between patients with primary melanoma and those with LR/IT disease. The rate in our study concurs with three studies (n = 100) examining SLNB in recurrent melanoma, where the aggregate rate of positive SLN in LR/IT was 38% (Table 2). Furthermore, 27% (12/44) of patients who were SLN-negative at the time of primary disease in this study had a positive SLN at surgery for LR/IT disease. The rate of 27% exceeds the expected rate of regional recurrence in previously negative node basins, reported to be 2.7–4.8%, suggesting some nodal metastasis occurring from the LR/IT.19,20

TABLE 2.

Results from studies examining SLNB in IT/LR melanoma

Study Total patients SLNB-positive [N (%)] No. with positive SLNB undergoing CLND [N (%)] CLND additional positive nodes [N (%)]
Yao et al.13 30 14 (46) 11 (79) 4/11 (36)
Gonzalez et al.9 55 20 (36) 14 (70) 4/14 (29)
Gipponi et al.11 15 4 (27) 4 (100) 2/4 (50)
Beasley [present study] 103 41 (40) 35 (85) 13/35 (37)
Total 203 79 (39) 64 (81) 23 (36)
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SLNB sentinel lymph node biopsy, LR locally recurrent, IT in-transit, CLND complete lymph node dissection

As a result of the higher rate of SLN positivity in LR/IT disease, many patients are upstaged in the AJCC 8th edition staging system.7 LR/IT disease with regional nodal disease is defined as stage IIIC (N2c or N3c), compared with LR/IT disease without regional nodal involvement, defined as stage IIIB (N1c).7 The prognostic significance of concurrent LN metastases also comes from data in patients undergoing HILP. The 10-year survival of patients undergoing HILP, and with IT disease without LN involvement, ranged from 41 to 56%, while those with IT disease and LN involvement ranged from 28 to 35%. Patients with no lymph node involvement undergoing HILP have consistently been reported to have a survival advantage over those with nodal involvement.21–24 Thus, we could expect that in an appropriately powered study population, patients with LR/IT melanoma and subclinical nodal involvement would likely have poorer prognosis than those without nodal involvement. This study can provide the basis for an appropriately powered prospective study.

In addition to prognostic information, SLNB can guide further surgical and systemic treatment options. For primary melanoma, the role of lymphadenectomy for SLN-positive disease is actively being studied, given that only 8–12% of patients who have a single positive sentinel node will have additional nodal metastases on CLND.25–27 The DeCOG-SLT phase III trial of CLND versus observation in patients with micrometastatic SLN (≤1 mm) showed no difference in distant MFS at 3 years between the observation group and the CLND group.28 Results from MSLT-2, which compares patients with positive SLNB managed with CLND versus nodal observation with ultrasound, are eagerly anticipated (25). CLND may soon no longer be routinely recommended for patients with primary melanoma and a positive SLN. However, patients in this study had a 37% (13/35) occurrence of having nonsentinel nodes involved at the time of CLND, consistent with a similar rate of 34% (10/29) across three prior studies (Table 2). Given the high rate of nonsentinel node positivity in the LR/IT population, patients with LR/IT disease with a positive SLNB should continue to be strongly considered for CLND.

Additionally, ipilimumab is now approved by the US FDA in the adjuvant setting for stage III resected melanoma with pathologic involvement of regional lymph nodes >1 mm, based on results of the randomized EORTC 18071 study comparing adjuvant ipilimumab with placebo, which found significantly improved 5-year OS (65 vs. 54%) in the ipilimumab arm compared with placebo.29 IT metastases alone are insufficient for this adjuvant indication. Given the associated toxicities of ipilimumab, including five toxicity-related deaths (1.1%) in EORTC 18071, patients with resected IT/LR disease may alternatively consider currently accruing and future adjuvant trials utilizing novel therapies, including anti-PD1 inhibitors (e.g., SWOG S1404, CheckMate 238).30,31 From a global perspective, patients with LR/IT disease and a positive SLNB may be treated with interferon-α2b. Determination of subclinical LN involvement with SLNB of IT/LR patients can not only appropriately stage patients for trial inclusion but can also allow more accurate interpretation of adjuvant trial results. Thus, the use of SLNB in patients with IT/LR can be used to identify patients who may benefit from adjuvant therapy. In particular, patients with IT/LR disease and positive SLNs may be more appropriate for systemic therapies.

Limitations of this study include its heterogeneous population and retrospective nature. In particular, specific details about the treatment of primary melanoma, as well as physical examination findings, could have allowed us more in-depth analyses. Due to the retrospective nature of the study, we were limited in the ability to analyse false-negative rates from SLNB for recurrent melanoma, and did not distinguish between local disease-free survival, regional lymph node disease survival, and distant MFS. We made the distinction between IT and LR disease (defined similar to satellite), although this has been viewed as arbitrary since the 2 cm rule has no anatomic or physiologic basis.32,33 Additionally, the management of 15 patients with multifocal IT disease (not resected at the time of SLNB) may be different compared with the other 92 patients who had lower disease burden and had resection of disease plus SLNB, especially their management, which included planned regional chemotherapy treatments that had been planned in those 15 patients.10

CONCLUSIONS

SLNB for LR or IT melanoma is technically feasible in patients with prior nodal sampling, and also for patients with prior LN dissections. SLNB can be performed concurrently with resection of recurrent disease when applicable.33 The rates of SLN positivity and nonsentinel node metastases in the setting of LR/IT disease appear to be higher than those of intermediate-thickness primary melanoma, and thus a larger portion of patients presenting with LR/IT disease will be eligible for adjuvant therapy, presently ipilimumab.29 The status of SLN in the setting of LR/IT disease is prognostic and has therapeutic implications. In the absence of distant metastatic disease or clinical nodal involvement, SLNB should be considered in patients presenting with IT or LR melanoma.

FUNDING

This study was supported in part by University of Virginia grant T32 CA163177 from the National Institutes of Health/National Cancer Institute (Yinin Hu).

Footnotes

CONFLICTS OF INTEREST Georgia M. Beasley, Yinin Hu, Linda Youngwirth, Randall P. Scheri, April Salama, Kara Rossfeld, Syed Gardezi, Doreen Agnese, J. Harrison Howard, Douglas Tyler, Craig L. Slingluff Jr, and Alicia Terando have no conflicts of interest to declare.

This work was presented at the 2017 Society of Surgical Oncology 70th Annual Cancer Symposium, Seattle, WA, USA, 15–18 March 2017.

REFERENCES

  • 1.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):1307–17. [DOI] [PubMed] [Google Scholar]
  • 2.Faries MB, Thompson JF, Cochran A. The impact on morbidity and length of stay of early versus delayed complete lymphadenectomy in melanoma: results of the Multicenter Selective Lymphadenectomy trial. Ann Surg Oncol. 2010;17(12):3324–29. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Morton DL, Hoon DS, Cochran AJ, Turner RR, Essner R, Takeuchi H et al. Lymphatic mapping and sentinel lymphadenectomy for early-stage melanoma: therapeutic utility and implications of nodal microanatomy and molecular staging for improving the accuracy of detection of nodal micometastases. Ann Surg. 2003;238(4):538–49; ; discussion 549-50. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.McMasters KM, Egger ME, Edwards MJ. Final results of the Sunbelt Melanoma Trial: a multi-institutional prospective randomized phase iii study evaluating the role of adjuvant high-dose interferon alfa-2b and completion lymph node dissection for patients staged by sentinel lymph node biopsy. J Clini Oncol. 2016;34(10):1079–86. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Pawlik TW, Ross MI, Johnson MM, Schacherer CW, McClain DM, Mansfield PF et al. Predictors and natural history of intransit melanoma after sentinel lymphadenectomy. Ann Surg Oncol. 2005;12(8):587–96. [DOI] [PubMed] [Google Scholar]
  • 6.Coit DG, Thompson JA, Andtbacka R, Anker CJ, Bichakjian CK, Carson WE, et al. Melanoma, version 4.2014. J Natl Compr Canc Netw. 2014;12:621–29. [DOI] [PubMed] [Google Scholar]
  • 7.Gershenwald JE, Scolyer RA, Hess KR. Melanoma of the skin. In: Alin MB, et al. editors. AJCC Cancer Staging Manual. 8th Ed. New York: Springer; 2017. [Google Scholar]
  • 8.Read RL, Haydu L, Saw RP, Quinn MJ, Shannon K, Spillane AJ, et al. In-transit melanoma metastases: incidence, prognosis, and the role of lymphadenectomy. Ann Surg Oncol. 2015;22(2):475–81. [DOI] [PubMed] [Google Scholar]
  • 9.Gonzalez AB, Jakub JW, Harmsen WS. Status of the regional nodal basin remains highly prognostic in melanoma patients with in-transit disease. J Am Coll Surg. 2016;223(1):77–85. [DOI] [PubMed] [Google Scholar]
  • 10.Beasley GM, Speicher PJ, Sharma K, Seigler H, Salama A, Mosca P, et al. Efficacy of repeat sentinel lymph node biopsy for patients who develop recurrent melanoma. J Am Coll Surg. 2014;218(4):686–92. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Gipponi M, Solari N, Giovinazzo D, Queirolo P, Bertoglio S, Villa G, et al. The role of sentinel lymph node biopsy in patients with local recurrence or in-transit metastasis of melanoma. Anticancer Res. 2014;34(6):3197–03. [PubMed] [Google Scholar]
  • 12.Dewar DJ, Powel BWEM. Sentinel node biopsy in patients with in-transit recurrence of malignant melanoma. Br J Plast Surg. 2003;56:415–17. [DOI] [PubMed] [Google Scholar]
  • 13.Yao KA, Hsueh EC, Essner R, Foshag LJ, Wanek LA, Morton DL, et al. Is sentinel lymph node mapping indicated for isolated local and in-transit recurrent melanoma? Ann Surg. 2003;238(5):743–47. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Hu Y, Melmer PD, Slingluff CL Jr. Localization of the sentinel lymph node in melanoma without blue dye. Ann Surg. 2016;262(3):588–92. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.McMasters KM, Reintgen DS, Ross MI. Sentinel lymph node biopsy for melanoma: how many radioactive nodes should be removed? Ann Surg Oncol. 2001;8:192–97. [DOI] [PubMed] [Google Scholar]
  • 16.Harlow SP, Krag DN, Ashikaga T, Weaver DL, Meijer SJ, Loggie BW, et al. Gamma probe guided biopsy of the sentinel node in malignant melanoma: a multicentre study. Melanoma Res. 2001;11(1):45–55. [DOI] [PubMed] [Google Scholar]
  • 17.Morton DL, Cochran AJ, Thompson JF Sentinel node biopsy in melanoma [letter]. N Engl J Med. 2007;356:419–20. [Google Scholar]
  • 18.Morton DL, Cochran AJ, Thompson JF. Authors’ response to a letter to the editor re: sentinel node biopsy for early-stage melanoma. Ann Surg. 2007;245:828–29. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Balch CM, Soong SI, Gershenwald JE, Thompson JF, Reintgen DS, Cascinelli N, et al. Prognostic factors analysis of 17,600 melanoma patients. Validation of the AJCC melanoma staging system. J Clin Oncol. 2001;19(16):3635–48. [DOI] [PubMed] [Google Scholar]
  • 20.Carlson GW, Page AJ, Cohen C, Parker D, Yaar R, Li A, et al. Regional recurrence after negative sentinel lymph node biopsy for melanoma. Ann Surg. 2008;248:378–386. [DOI] [PubMed] [Google Scholar]
  • 21.Bass P, Schrafford Koops H, Haekstra H. Isolated regional perfusion in the treatment of melanoma of the extremities. Reg Cancer Treat. 1988;1:33–36. [Google Scholar]
  • 22.Grünhagen DJ, Brunstein F, Graveland WJ, van Geel AN, de Wilt JH, Eggermont AM. One hundred consecutive isolated limb perfusions with TNF-alpha and melphalan in melanoma patients with multiple in-transit metastases. Ann Surg. 2004;240:939–47. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Noorda EM, Vrouenraets BC, Nieweg OE, van Geel BN, Eggermont AM, Kroon BB. Isolated limb perfusion for unresectable melanoma of the extremities. Arch Surg. 2004;139:1237–42. [DOI] [PubMed] [Google Scholar]
  • 24.Di Filippo F, Giacomini P, Rossi CR, Santinami M, Anza M, Garinei R, et al. Prognostic factors influencing tumor response, locoregional control and survival, in melanoma patients with multiple limb in-transit metastases treated with TNFα-based isolated limb perfusion. In Vivo. 2009;23:347–52. [PubMed] [Google Scholar]
  • 25.Morton DL. Overview and update of the phase III multicenter selective lymphadenectomy trials (MSLT-I and MSLT-II) in melanoma. Clin Exp Metastasis. 2012;29(7):699–06. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.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 early-stage melanoma: a multicenter trial. Multicenter Selective Lymphadenectomy Trial Group. Ann Surg. 1999;230(4):453–63; discussion 63–65. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Cochran AJ, Wen DR, Huang RR, Wang HJ, Elashoff R, Morton DL. Prediction of metastatic melanoma in nonsentinel nodes and clinical outcome based on the primary melanoma and the sentinel node. Mod Pathol. 2004; 17:747–55. [DOI] [PubMed] [Google Scholar]
  • 28.Leiter U, Stadler R, Mauch C, Hohenberger W, Brockmeyer N, Berking C, et al. Complete lymph node dissection versus no dissection in patients with sentinel lymph node biopsy positive melanoma (DeCOG-SLT): a multicentre, randomised, phase 3 trial. Lancet Oncol. 2016; 17(6):757–67. [DOI] [PubMed] [Google Scholar]
  • 29.Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med. 2016;375:1845–55. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Grossmann KF, Othus M, Tarhini AA, et al. SWOG S1404: a phase III randomized trial comparing standard of care adjuvant therapy to pembrolizumab in patients with high risk resected melanoma [abstract no. e21032]. J Clin Oncol. 2016;34 Suppl [Google Scholar]
  • 31.Weber J, Grob JJ, Margolin KA, Ascierto PA, Sznol M, Ott PA, et al. A phase III study (CheckMate 238) of adjuvant immunotherapy with nivolumab (NIVO) versus ipilimumab (IPI) after complete resection of stage IIIb/c or stage IV melanoma (MEL) in patients (pts) at high risk for recurrence. J Immunother Cancer. 2015; 3(Suppl 2):P166. [Google Scholar]
  • 32.Buzaid AC, Ross MI, Balch CM, Soong SJ, McCarthy WH, Tinoco L, et al. Critical analysis of the current American Joint Committee on cancer staging system for cutaneous melanoma and proposal of a new staging system. J Clin Oncol. 1997;15(3):1039–51. [DOI] [PubMed] [Google Scholar]
  • 33.Wrighston 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):676–80. [DOI] [PubMed] [Google Scholar]

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