patients who had undergone narrower margin excision for tumours of varying Breslow thickness.34–40 These studies suggested that margins narrower than 4-5cm could be taken without increasing the risk of local recurrence. However, they also demonstrated an increased rate of local recurrence when very narrow (<0.5cm) margins were taken. Prospective randomised studies were therefore required and to date there have been six published trials.41–46 The details of the published randomised trials are documented in Table 1.1.2. Table 1.1.2. Completed randomized trials comparing excision margins for melanoma. Study Period of Excision margins compared Number of patients Primary thickness inclusion criteria Primary melanoma sites and/or subtypes excluded Overall survival Fat World Health Organization 1cm vs 3cm 1-2cm wider than skin excision 703 ≤2mm At 8yrs 89.6% (1cm) vs 90.3% (3cm), p =0.64 French Group44 2cm vs 5cm down to muscle fascia 337 <2mm, age <70 Toe, nail, finger lesions, arising form melanosis, lentigo and acral lesions. At 10yrs 87% (2cm) vs 85% (5cm), p=0.56 Intergroup Melanoma Trial42,49 Not stated 2cm vs 4 cm Same as skin down to or including fascia 486* 470* 468* 1 to 4 mm Lentigo maligna melanoma, distal to knee or elbow or on head and neck At 10 yrs 70% (2cm) vs 77% (4cm), p=0.07 Swedish Melanoma Study Group43,50 2cm vs 5 cm Incisions extended to or included fascia 989 >0.8 to 2mm Head and neck, hands, feet. At 10 yrs 79% (2cm) vs 76% (5cm), UK Melanoma Study Group45 1cm vs Not stated 900 ≥2mm Head and neck, No significant operative 2001 n n 1985
Breslow thickness of 1.00mm or more or of Clark level IV or V with any Breslow thickness were eligible for inclusion, but patients with intermediate thickness melanoma (1.20 to 3.50mm) were the primary study group. Two thousand and one patients were registered and enrollment closed in 2002. The randomisation process assigned 60% of patients to the wide excision and sentinel node biopsy group and 40% of patients to the wide excision and nodal observation group. In the intermediate thickness group there were 1347 patients with 814 in the sentinel node biopsy group and 533 in the nodal observation group. There was just over 4% cross over from each arm with 35 patients in the sentinel node biopsy group actually undergoing observation and 22 patients in the nodal observation group actually having sentinel node biopsy. Sentinel node biopsy was shown to accurately detect occult nodal disease in 96% of cases and sentinel node status was confirmed as the most powerful predictor of survival in the study population. The 10-year melanoma-specific survival rate (mean +/- standard error) for the biopsy group was 81.4+/-1.5% versus 78.3+/-2.0% for the observation group. This difference was not statistically significant. One of the problems with this trial was that the ideal comparison groups (sentinel node positive patients versus patients who develop nodal recurrence in the observation group) could not be identified prior to the point of randomisation and so statistical comparison of melanoma-specific survival for these two groups could be affected by bias. In order to compare these two groups and to account for potential bias the authors employed a statistical method called latent subgroup analysis and found that the melanoma-specific survival time for sentinel node positive patients in the sentinel node biopsy group was double that of patients who developed nodal recurrence in the nodal observation group. This finding was the case only in the intermediate thickness melanoma group. In the thick melanoma group (>3.50mm) there was no significant difference in survival and in the thin melanoma group (<1.20mm) there were relatively few cases with nodal disease and so statistical analysis was not reported. THE SIGNIFICANCE OF NODAL METASTASIS BEYOND SENTINEL NODES
histological analysis of the sentinel node in 2 cases, failure to identify an interval node in 1 case, initial in-transit metastasis prior to nodal recurrence in 1 case and systemic recurrence with nodal disease in 3 cases. The importance of the method of wound closure or reconstruction following wide local excision was identified as a likely cause in 4 cases, in which a rotation flap, a flap which would have involved fairly extensive incisions and significant tissue undermining, was used. In summary, the evidence suggests that for patients with primary melanoma on the trunk or extremities who have already undergone wide local excision, lymphoscintigraphy and sentinel node biopsy remain reliable, provided that a rotational flap has not been used in reconstruction. For patients with head and neck melanoma there is inadequate data to support this view and, given the high concentration of lymphatic drainage pathways in this region, there may be a higher likelihood of altered lymphatic drainage as a result of wide local excision. Table 1.3.1. Summary of studies examining the validity of lymphoscintigraphy and sentinel node biopsy for patients who have undergone previous wide local excision. Publication Number of patients Tumour locations Number of patients with positive SNs Number of false negative SN biopsies Likely cause for false negative SN biopsies Karakousis and Grigoropoulos, 1999 196 All sites 9 1 Rotation flap Kelemen et al., 1999 195 47 All sites 11 3 Histology error in 2 cases + metastasis in other case McCready et al., 199 100 Head + neck excluded 31 3 Rotation flap in 2 cases Leong et al., 2003 201 24 Limbs only 2 1 Interval node missed Leong, Ghazarian and McCready, 2003 200 65 Head + neck excluded 21 1 Rotation flap
65 F 1992 Right region Primary site over regional nodes Apparent No None at 10 years 45 F 1994 Right neck Primary site over regional nodes Apparent Yes (negative) None at 11 years 66 M 1999 Right axilla Primary site over regional nodes Apparent No Right axilla 77 F 2001 Right cheek No cause identified True Unknown Unknown 57 F 2001 Right posterior shoulder Previous right axillary dissection True or apparent No None at 5 years 77 F 2001 Right neck a) Excision biopsy site infection b) Primary site over regional nodes c) Previous sternotomy. a) True b) Apparent c) True No. No focal hot spot found with gamma probe None at 3 years 75 M 2001 Left thorax posterior Excision biopsy site inflamed + dehisced True No Died 9 months later, cause unknown 25 F 2002 Left Primary site over regional nodes Apparent or true (close to thoracic duct) No None recorded 52 F 2002 Left axilla Primary site over regional nodes Apparent No Left axilla Table 2.1.3. Details of cases where failure to identify sentinel nodes (non-localization) by lymphoscintigraphy occurred. Table 2.1.3 (continued) Age Sex Date of LSG Location of primary tumour Likely cause for failure to identify SNs Category of SN biopsy performed? Site of any recurrence
only Wright (2010)171 Hull, UK Retrospective, observational Not stated Not stated (range years) 49 Yes Does not state type of analysis Baehner (2012)172 San Francisco, USA Review of prospective database 81.6 63 Yes Did not investigate NSN status in multivariate analysis and did not account for total number of positive nodes in survival curve comparison Patuzzo (2015)173 Milan, Italy Retrospective, observational Not stated 1096 Yes No details of statistical analysis (conference abstract) SN = sentinel node, NSN = non-sentinel node. Table 3.1.2. Studies that met the inclusion criteria and were included in the critical review (n=11). 1st Author (year of publication) Setting Study type Period of study Median follow-up (months) Number of SN positive patients Number of NSN positive patients (%) Outcome worse if NSN positive? Cascinelli (2006)149 Milan, Italy Review of prospective database 1994-2005 61.1 176 33 (18.7) Yes Ariyan (2008)174 New York, USA Review of prospective database 1991-2006 33 222 37 (16.7) Yes Ghaferi (2009)175 Michigan, USA Review of prospective database 1997- not stated 36.8 419 71 (16.9) Yes Jakub (2009)164 Florida, USA Review of prospective database 1998-2006 Not stated (mean 38.9) 229 46 (20.1) Yes Wiener (2010)161 Sydney, Australia Review of prospective database 1992-2005 40 323 60 (18.6) Yes Brown (2010)176 SUNBELT trial (USA and Canada) Post-hoc analysis of trial database 1997-2003 with analysis of follow-up data until 2009 68 347 51 (14.7) Yes Eggera (2013) (Ann Surg Oncol)178 SUNBELT trial (USA and Canada) Post-hoc analysis of trial database Not stated (1997-2003 = trial enrollment period) 58 509 51 (10.0) Yes Reintgen (2013)179 Florida, USA Review of prospective database 1990-2011 Not stated (mean 42) 331 61 (18.4) Yes Leung (2013)180 California, USA Review of prospective database 1986-2012 Not stated 329 79 (24%) Yes
field) Primary tumor histology unable to be reviewed by SMU3 histopathologist 8 SNB or CLND performed by non-SMU surgeon 14 TOTAL EXCLUDED 178 1SNB=sentinel node biopsy 2CLND=completion lymph node dissection 3SMU=Sydney Melanoma Unit Table 3.2.2. Characteristics of study patients (n=323) Characteristic Mean ± SD or (%) Age at SNB1 52.3 ± 16.9 Gender Male Female 198 (61.3) 125 (38.7) Tumor thickness (mm) ≤2.0 2.1-4.0 >4.0 96 (30.0) 133 (41.7) 90 (28.2) Ulceration No Yes 173 (56.7) 132 (43.3) Mitotic rate (mitoses/mm2) ≤5 6-10 >10 191 (60.8) 70 (22.3) 53 (16.9)
Location of primary melanoma Trunk Extremity Head and neck Others 115 (35.6) 168 (52.0) 39 (12.1) 1 ( 0.3) 1SNB=sentinel node biopsy Table 3.2.3. Distribution of positive nodes within the study population SN+NSN SN NSN (%) 1 1 0 210 (64.8) 2 1 1 27 (8.3) 2 0 44 (13.6) 3 1 2 12 (3.7) 2 1 11 (3.4) 3 0 8 (2.5) 4 1 3 4 (0.9) 2 2 1 (0.3) 3 1 1 (0.3) 4 0 1 (0.3) 5 1 4 1 (0.3) 2 3 1 (0.3) 7 1 6 1 (0.3) 8 4 4 1 (0.3) SN = sentinel node NSN = non-sentinel node n = number of patients
Table 3.2.5. Distributions of characteristics and logistic model results regarding presence of positive non-sentinel nodes (NSNs) Metastasis found in NSN(s)? Univariate Multivariate Characteristic No (N=263) N (%) Yes (N=60) N (%) Crude OR (95%CI) Adjusted OR (95%CI) Age at SNB#*$ 51.7 ± 16.9 54.7 ± 17.2 1.11 0.224 1.08 0.406 Gender Male Female 157 (79.3) 106 (84.8) 41(20.7) 19(15.2) 1 0.69 0.217 1 0.73 0.319 Tumor thickness (mm) ≤2.0 2.1-4.0 >4.0 79 (82.3) 110 (82.7) 70 (77.8) 17 (17.7) 23 (17.3) 20 (22.2) 1 0.97 1.33 0.935 0.442 1 0.45 0.68 0.061 0.376 Ulceration No Yes 149 (86.1) 97 (73.5) 24(13.9) 35(26.5) 1 2.24 0.006 1 2.06 0.042 Mitotic rate (mitoses/mm2) ≤5 6-10 >10 163 (85.3) 54 (76.1) 38 (71.7) 28 (14.7) 16 (22.9) 15 (28.3) 1 1.73 2.30 0.120 0.024 1 1.75 2.02 0.137 0.092 Number of sentinel nodes removed 2.1 ± 1.1 1.8 ± 1.0 0.80 0.119 0.79 0.124 # SNB=sentinel node biopsy *Mean ± SD $ Adjusted odds ratio for age in 10 year increments Figure 3.2.5. Survival tree model for sentinel node (SN) positive patients (non-sentinel node = NSN; sentinel node biopsy = SNB).