Abstract
Background
Guidelines for melanoma recommend sentinel lymph node biopsy (SLNB) in patients with melanomas ≥1 mm thickness. Recent single institution studies have found tumors <1.5 mm a low-risk group for positive SLNB.
Methods
A retrospective review of the Sentinel Lymph Node Working Group multicenter database identified patients with intermediate thickness melanoma (1.01–4.00 mm) who had SLNB, and assessed predictors for positive SLNB.
Results
3460 patients were analyzed, 584 (17%) had a positive SLNB. Univariate factors associated with a positive SLNB included age <60 (p < .001), tumor on the trunk/lower extremity (p < .001), Breslow depth ≥2 mm (p < .001), ulceration (p < .001), mitotic rate ≥1/mm2 (p = .01), and microsatellitosis (p < .001). Multivariate analysis revealed age, location, and Breslow depth as significant predictors. Patients ≥75 with lesions 1.01–1.49 mm on the head/neck/upper extremity and 1.5–1.99 mm without high-risk features had <5% risk of SLN positivity.
Conclusions
Intermediate thickness melanoma has significant heterogeneity of SLNB positivity. Low-risk subgroups can be found among older patients in the absence of high-risk features.
1. Introduction
An estimated 76,380 new cases of melanoma will be diagnosed in the United States in 2016.1 These patients will undergo a comprehensive assessment of their disease to determine their prognosis and potential treatment. The most important prognostic factor is the presence of lymph node metastases.2,3 Historically, elective lymph node dissection was used to determine whether the patient had lymph node metastases but subsequently lymphoscintigraphy had demonstrated that elective lymph node dissection may miss a significant amount of disease in the face of the morbidity of lymph node dissection. Lymphatic mapping of melanoma showed nodal metastases from cutaneous melanoma were not random but followed specific lymphatic pathway(s), and the histology of the sentinel node(s) removed accurately reflected the biology of the remaining lymphatic basin.4 A variety of studies embarked on proving the feasibility and efficacy of sentinel lymph node biopsy (SLNB) for identifying patients at high-risk of nodal metastases and targeting patients in whom completion lymphadenectomy may be warranted.5 SLNB has been found to have prognostic value and it has been shown to offer a survival benefit over observation alone.2,6,7
Staging of melanoma using SLNB has revolutionized the field, improving patient selection for lymph node dissection. Lymph node metastasis is the single most important prognostic factor for patients with localized melanoma.2,8 In patients with thin melanomas (<1 mm), sentinel lymph node biopsy is considered for those with melanomas > 0.75 mm and/or those with high risk features.9–12 Prior studies have reported SLNB+ rates of around 15–25% in intermediate thickness melanoma.2,13–15 Overall, sentinel lymph node biopsy has been associated with low morbidity compared to elective lymphadenectomy.16,17
National Comprehensive Cancer Network (NCCN) guidelines currently recommend SLNB for all patients with intermediate thickness melanomas (1.01–4.00 mm).18 Recently published work by Bartlett et al. has identified subgroups of patients (absent LVI, absent mitoses, and either absent regression or age of 60 and older) with intermediate thickness melanoma who may be at similarly low risk (<5%) for a positive sentinel lymph node biopsy as thin melanoma groups.13 Particularly in the older population of patients, the question arises as to who may be spared a SLNB. Similarly, prior papers have found the presence or absence of high-risk histopathologic features such as ulceration and lymphovascular invasion to be predictors of a positive sentinel lymph node biopsy.14,19,20 To answer these questions, our group queried a large, retrospective, multicenter database.
Our study had two aims: first, could we stratify patients with intermediate thickness melanoma based upon prognostic factors to determine sentinel lymph node positivity to identify clinically significant subgroups which may be groups of patients in clinical practice who may be spared a sentinel lymph node biopsy based on a low pre-test probability of a positive sentinel node. Second, certain patients (≥75) are burdened with significant co-morbidities, can we identify subgroups that may be at low risk for a positive SLNB and therefore have the opportunity to decrease their surgical morbidity. The age of 75 was a group consensus regarding the age at which co-morbidities were more likely to influence clinical decision making.21
2. Materials and methods
The Sentinel Lymph Node Working Group (SLNWG) consists of 7 member institutions. All members obtained approval from their respective institutional review boards before submitting patients for this retrospective study. Informed consent was obtained from all patients except where waiver of informed consent was granted by the institutional review board for retrospective data collection. The SLNWG database is maintained at the Mayo Clinic in Phoenix, Arizona. Patient data are submitted by each member institution through a password-protected Web site into this standardized database.
SLN biopsy was performed as previously described using blue dye, radioactive colloid, or both. Indications for SLN biopsy and specific operative techniques were determined by individual investigators. In general, the investigators in this multicenter study used a combination of radioactive colloid and blue dye with preoperative lymphoscintigraphy.
Patients from 1993 to 2015 were identified with intermediate thickness melanoma (1.01–4.0 mm) and their demographic information and tumor characteristics were analyzed for factors predictive of sentinel lymph node positivity. A positive sentinel lymph node was defined as any malignant cells identified in the specimen.
2.1. Statistical analysis
Descriptive statistics were used to summarize results by negative or positive sentinel lymph node biopsy. Patient demographics and tumor characteristics were compared between categories by analysis of variance (ANOVA) for continuous variables or chi-square tests for categorical variables. Statistical analysis to assess the predictive variables included univariate logistic regression and multivariable forward selection logistic regression models. Variables in which p < .20 in univariate analysis were considered for inclusion in the multivariable model. This included age group, location, thickness, Clark level, ulceration, lymphvascular invasion and mitotic rate. Adjusted odds ratios (OR) and 95% confidence intervals were calculated. A second multivariate analysis was performed using age of ≥75 to determine predictive factors in this population. Two-sided p-value <.05 were considered statistically significant.
3. Results
3.1. Patient and tumor characteristics (Table 1)
Table 1.
Patient and tumor characteristics.d
| SLNB−c (N = 2876) |
SLNB+c (N = 584) |
Total (N = 3460) |
p value | |
|---|---|---|---|---|
| Age | <.0001a | |||
| Mean (SD) | 57.8 (16.3) | 53.8 (16.8) | 57.1 (16.4) | |
| Interquartile Range | (46.0–70.9) | (41.7–66.4) | (45.2–70.0) | |
| Age Group | <.0001b | |||
| <60 | 1486 (53%) | 364 (63%) | 1850 (55%) | |
| 60–74 | 879 (31%) | 143 (25%) | 1022 (30%) | |
| 75+ | 447 (16%) | 70 (12%) | 517 (15%) | |
| Gender | .4682b | |||
| Male | 1677 (58%) | 350 (60%) | 2027 (59%) | |
| Race | .9177b | |||
| Caucasian | 2640 (99%) | 537 (99%) | 3177 (99%) | |
| African American | 5 (0.2%) | 1 (0.2%) | 6 (0.2%) | |
| Hispanic | 11 (0.4%) | 2 (0.4%) | 13 (0.4%) | |
| Asian | 10 (0.4%) | 3 (0.6%) | 13 (0.4%) | |
| Native American/Alaskan | 2 (0.1%) | 1 (0.2%) | 3 (0.1%) | |
| Lesion Site | <.0001b | |||
| Head/Neck | 567 (20%) | 76 (13%) | 643 (19%) | |
| Upper Extremity | 645 (22%) | 91 (16%) | 736 (21%) | |
| Lower Extremity | 682 (24%) | 169 (29%) | 851 (25%) | |
| Trunk | 980 (34%) | 247 (42%) | 1227 (36%) | |
| Breslow Thickness | <.0001a | |||
| N | 2876 | 584 | 3460 | |
| Mean (SD) | 1.9 (0.8) | 2.3 (0.8) | 2.0 (0.8) | |
| Range | (1.0–4.0) | (1.0–4.0) | (1.0–4.0) | |
| Breslow Thickness Group | <.0001b | |||
| 1.01–1.49 | 1071 (37%) | 126 (22%) | 1197 (35%) | |
| 1.50–1.99 | 655 (23%) | 115 (20%) | 770 (22%) | |
| 2.0–2.99 | 760 (26%) | 209 (36%) | 969 (28%) | |
| 3.0–4.0 | 390 (14%) | 134 (23%) | 524 (15%) | |
| Breslow Thickness Group | <.00012 | |||
| 1.01–1.99 | 1726 (60%) | 241 (41%) | 1967 (57%) | |
| 2.0–2.99 | 760 (26%) | 209 (36%) | 969 (28%) | |
| 3.0–4.0 | 390 (14%) | 134 (23%) | 524 (15%) | |
| Clark Level Group | .0034b | |||
| II/III | 612 (29%) | 98 (22%) | 710 (27%) | |
| IV/V | 1532 (72%) | 352 (78%) | 1884 (73%) | |
| Ulceration | <.0001b | |||
| Present | 656 (27%) | 186 (37%) | 842 (29%) | |
| Lymphovascular Invasion | <.0001b | |||
| Present | 123 (8%) | 58 (17%) | 181 (10%) | |
| Mitotic rate (per mm2) | .0108b | |||
| <1 | 182 (12%) | 24 (7%) | 206 (11%) | |
| ≥1 | 1352 (88%) | 315 (93%) | 1667 (89%) | |
| Tumor regression | .3502b | |||
| Present | 253 (18%) | 45 (15%) | 298 (17%) | |
| Microsatellitosis | <.0001b | |||
| Present | 42 (3%) | 32 (9%) | 74 (4%) | |
| Tumor-infiltrating Lymphocytes | .2978b | |||
| Present | 844 (77%) | 164 (74%) | 1008 (76%) | |
ANOVA F-Test.
Chi-Square.
SLNB-Sentinel Lymph Node Biopsy.
Not all patients had full complement of data points.
A total of 3460 patients were identified and included in the analysis. Overall positive sentinel lymph node biopsy (SLNB) rate was 17%. The median age was 57.8 (mean 57.1). 59% (n = 2027) were male, and 99% (n = 3177) patients were Caucasian. Patients with positive SLNB were more likely to be younger (p < .0001). No difference was seen in positive SLNB rates regarding gender (p = .47) or race (p = .92). Patients with tumors located on the head or neck (HN), or upper extremity (UE) were significantly less likely to have a positive SLNB than patients with lesions located on the trunk (TK) or lower extremity (LE) (p < .0001). Thicker lesions were more likely to have a positive SLNB (p < .0001). In the subgroup of patients with melanoma between 1.01 and 1.99 mm, a statistical difference was found between patients from 1.01 to 1.49 mm and 1.5–1.99 mm (p < .0001). Melanomas with a Clark’s level of IV/V were more likely to be associated with a positive SLNB (p = .0034). Ulceration (p < .0001), lymphovascular invasion (p < .0001), mitotic rate (p = .011), and microsatellitosis (p < .0001). Tumor regression (p = .35) and tumor infiltrating lymphocytes (p = .30) were not found to have an association with SLN status, however information regarding tumor regression was available in 50% of patients (n = 1723), and 38% of patients had tumor infiltrating lymphocyte information available (n = 1322).
3.2. Predictive factors for a positive sentinel lymph node biopsy (Table 2)
Table 2.
Predictive factors for a positive sentinel lymph node biopsy.
| Prognostic Factor | Univariate Analysis | p-value | Multivariate Analysis | p-value | |||
|---|---|---|---|---|---|---|---|
|
| |||||||
| n (%) |
Odds ratio | 95% Confidence Interval | Odds ratio | 95% Confidence Interval | |||
| Age Group | |||||||
| <60 | 1850 (55%) |
Ref | |||||
| 60–74 | 1022 (30%) |
0.66 | 0.54–0.82 | <.001 | 0.45 | 0.30–0.67 | <0.001 |
| 75+ | 517 (15%) |
0.64 | 0.48–0.84 | .002 | 0.48 | 0.28–0.82 | 0.007 |
| Gender | |||||||
| Female | 1427 (41%) |
Ref | |||||
| Male | 2027 (59%) |
1.07 | 0.89–1.28 | .468 | |||
| Location | |||||||
| Head/Neck | 643 (19%) |
Ref | |||||
| Lower Extremity | 851 (25%) |
1.85 | 1.38–2.48 | <.001 | 2.15 | 1.20–3.86 | 0.010 |
| Upper Extremity | 736 (21%) |
1.05 | 0.76–1.46 | .757 | 1.65 | 0.86–3.16 | 0.132 |
| Trunk | 1227 (36%) |
1.88 | 1.43–2.48 | <.001 | 2.12 | 1.21–3.71 | 0.009 |
| Breslow Thickness (mm) | |||||||
| 1.01–1.49 | 1197 (35%) |
Ref | |||||
| 1.50–1.99 | 770 (22%) |
1.49 | 1.14–1.96 | .004 | 1.43 | 0.86–2.36 | 0.168 |
| 2.00–2.99 | 969 (28%) |
2.34 | 1.84–2.97 | <.001 | 2.73 | 1.72–4.34 | <0.001 |
| 3.00–4.00 | 524 (15%) |
2.92 | 2.23–3.82 | <.001 | 3.60 | 2.14–6.05 | <0.001 |
| Breslow Thickness (mm) | |||||||
| 1.01–1.99 | 1967 (57%) |
Ref | |||||
| 2.00–2.99 | 969 (28%) |
1.97 | 1.61–2.42 | <.001 | 2.31 | 1.57–3.41 | <0.001 |
| 3.00–4.00 | 524 (15%) |
2.46 | 1.94–3.12 | <.001 | 3.04 | 1.93–4.79 | <0.001 |
| Clark Level | |||||||
| II/III | 710 (27%) |
||||||
| IV/V | 1884 (73%) |
1.43 | 1.12–1.83 | .004 | |||
| Ulceration | |||||||
| Absent | 2073 (71%) |
Ref | |||||
| Present | 842 (29%) |
1.56 | 1.27–1.91 | <.001 | |||
| Lymphovascular Invasion | |||||||
| Absent | 1705 (90%) |
Ref | |||||
| Present | 181 (10%) |
2.43 | 1.73–3.41 | <.001 | |||
| Tumor Mitotic Rate (per mm2) | |||||||
| <1 | 206 (11%) |
Ref | |||||
| ≥1 | 1667 (89%) |
1.77 | 1.16–2.82 | .012 | |||
| Regression | |||||||
| Absent | 1425 (83%) |
Ref | |||||
| Present | 298 (17%) |
0.85 | 0.60–1.20 | .351 | |||
| Microsatellitosis | |||||||
| Absent | 1917 (96%) |
Ref | |||||
| Present | 74 (4%) |
3.85 | 2.39–6.19 | <.001 | 2.31 | 1.09–4.89 | 0.029 |
| Tumor Lymphocytes | |||||||
| Absent | 314 (24%) |
Ref | |||||
| Present | 1008 (76%) |
0.84 | 0.60, 1.17 | .298 | |||
Age, location, Breslow thickness, Clark level, and high-risk features such as ulceration, lymphovascular invasion, mitotic rate and microsatellitosis were all significant in univariate logistic regression analysis. Significant factors included: age 60–74 and age ≥75, location on the lower extremity and trunk, Clark level IV/V, ulceration, lymphovascular invasion, mitotic rate ≥1/mm2, and microsatellitosis, Breslow thickness 2–2.99 mm vs 3–4.00 mm. Breslow thickness was also found to be predictive of a positive SNLB.
The factors that remained predictive of sentinel lymph node positivity in multivariate analysis were: age 60–74, age ≥75, location on the lower extremity or trunk, Breslow thickness >2, and microsatellitosis.
We then evaluated a model focusing on the effect of a poor prognostic features (ulceration, lymphovascular invasion, mitotic rate ≥1, and/or microsatellitosis) as determined by the univariate analysis. We divided patients by age ≥ or <60, Breslow thickness, tumor location, and presence or absence of high-risk features (Table 4). Only patients younger than 60, with tumors 1.5–1.99 mm, located on the head/neck/upper extremity, without high risk features had a positive sentinel lymph node biopsy rate of less than 5% (n = 65, 95% confidence interval 0.9–12.9%). Interestingly, the impact of poor prognostic features appeared to lose significance in patients ≥60 years, with minimal increase in positive sentinel lymph node rate dependent on the presence or absence of high-risk features.
Table 4.
Elderly patient (≥75) characteristics and prognostic factors.
| SLNB− (n = 447) |
SLNB+ (n = 70) |
Total (n = 517) |
p value | |
|---|---|---|---|---|
| Age | .5608a | |||
| Mean (SD) | 80.7 (4.3) | 80.3 (6.4) | 80.6 (4.6) | |
| Range | (75.0–97.2) | (75.0–125.5) | (75.0–125.5) | |
| Gender | .6888b | |||
| Male | 289 (65%) | 43 (62%) | 332 (65%) | |
| Race | .7504b | |||
| Caucasian | 415 (98%) | 67 (99%) | 482 (98%) | |
| African American | 2 (0.5%) | 0 (0.0%) | 2 (0.4%) | |
| Hispanic | 3 (0.7%) | 0 (0.0%) | 3 (0.6%) | |
| Asian | 2 (0.5%) | 1 (1.5%) | 3 (0.6%) | |
| Native American/Alaskan | 1 (0.2%) | 0 (0.0%) | 1 (0.2%) | |
| Lesion Site | .5015b | |||
| Head/Neck | 130 (29%) | 17 (24%) | 147 (28%) | |
| Upper Extremity | 110 (25%) | 20 (29%) | 130 (25%) | |
| Lower Extremity | 105 (24%) | 13 (19%) | 118 (23%) | |
| Trunk | 102 (23%) | 20 (29%) | 122 (24%) | |
| Breslow Thickness | .0305a | |||
| N | 447 | 70 | 517 | |
| Mean (SD) | 2.2 (0.8) | 2.4 (0.7) | 2.2 (0.8) | |
| Range | (1.0–4.0) | (1.1–4.0) | (1.0–4.0) | |
| Breslow Thickness Group | .0366b | |||
| 1.01–1.49 | 113 (25%) | 10 (14%) | 123 (24%) | |
| 1.50–1.99 | 94 (21%) | 10 (14%) | 104 (20%) | |
| 2.0–2.99 | 140 (31%) | 32 (46%) | 172 (33%) | |
| 3.0–4.0 | 100 (22%) | 18 (26%) | 118 (23%) | |
| Breslow Thickness Group | .0150b | |||
| 1.01–1.99 | 207 (46%) | 20 (29%) | 227 (44%) | |
| 2.0–2.99 | 140 (31%) | 32 (46%) | 172 (33%) | |
| 3.0–4.0 | 100 (22%) | 18 (26%) | 118 (23%) | |
| Clark Level Group | .0728b | |||
| II/III | 56 (17%) | 4 (7%) | 60 (16%) | |
| IV/V | 274 (83%) | 50 (93%) | 324 (84%) | |
| Ulceration | .0887b | |||
| Present | 134 (34%) | 27 (46%) | 161 (36%) | |
| Lymphovascular invasion | .0001b | |||
| Present | 16 (7%) | 10 (27%) | 26 (9%) | |
| Mitotic rate (per mm2) | .4771b | |||
| <1 | 28 (11%) | 3 (7%) | 31 (11%) | |
| ≥1 | 227 (89%) | 38 (93%) | 265 (89%) | |
| Tumor regression | .5090b | |||
| Present | 40 (18%) | 5 (14%) | 45 (18%) | |
| Microsatellitosis | .0101b | |||
| Present | 10 (4%) | 6 (13%) | 16 (5%) | |
| Tumor-infiltrating lymphocytes | .2784b | |||
| Present | 121 (70%) | 24 (80%) | 145 (72%) | |
| Prognostic Factor | Multivariate Analysis | |||
| Odds ratio | 95% CI | p value | ||
| Vascular invasion | ||||
| Yes | 4.43 | 1.68–11.69 | .003 | |
Multivariate Forward Logistic Regression Analysis.
ANOVA F-Test.
Chi-Square.
3.3. Older patients (Table 4)
Patients ≥ 75 were examined separately as a group. This group had an overall positive SLNB rate of 12.1%. Of note, the rate of SLNB positivity decreased with age ≥60, but did not reach significance when comparing age groups 60–69 vs 70–79 vs 80+ years old (p = .60). Patients ≥75 years were more likely to have thicker tumors (p = .037), lymphovascular invasion present (p = .0001), and microsatellitosis (p = .01). Multivariate logistic regression revealed only the presence of lymphovascular invasion as being significant. A similar model was performed on the ≥75 year old patient group dividing patients by age ≥ or <75, Breslow thickness, tumor location, and presence or absence of high-risk features (Table 3). This analysis identified a small group of patients who had a low incidence of SLN positivity of <5% who were ≥75 years of age with a head and neck/upper extremity melanoma of 1.0–1.49 mm with or without poor prognostic features (n = 66) or a thickness of 1.5–1.99 mm without high-risk features (n = 37).
Table 3.
Patients stratified by age, thickness, location, and presence/absence of high risk features.
| Age | Thickness(mm) | Location | High-risk featuresa | SLNB+ (%) | n |
|---|---|---|---|---|---|
| <60 | 1.01–1.49 | Head/neck/upper extremity | None | 6.5 | 123 |
| At least one | 11.9 | 118 | |||
| Trunk/lower extremity | None | 9.4 | 233 | ||
| At least one | 16.4 | 232 | |||
| 1.50–1.99 | Head/neck/upper extremity | None | 4.6 | 65 | |
| At least one | 9.8 | 61 | |||
| Trunk/lower extremity | None | 21.8 | 124 | ||
| At least one | 26.0 | 177 | |||
| 2.0–2.99 | Head/neck/upper extremity | None | 10.3 | 58 | |
| At least one | 21.4 | 103 | |||
| Trunk/lower extremity | None | 27.1 | 107 | ||
| At least one | 30.1 | 206 | |||
| 3.0–4.0 | Head/neck/upper extremity | None | 17.9 | 28 | |
| At least one | 26.2 | 61 | |||
| Trunk/lower extremity | None | 24.4 | 41 | ||
| At least one | 43.8 | 112 | |||
| ≥60 | 1.01–1.49 | Head/neck/upper extremity | None | 7.9 | 101 |
| At least one | 6.9 | 131 | |||
| Trunk/lower extremity | None | 10.8 | 111 | ||
| At least one | 11.4 | 123 | |||
| 1.50–1.99 | Head/neck/upper extremity | None | 7.5 | 53 | |
| At least one | 9.8 | 102 | |||
| Trunk/lower extremity | None | 7.5 | 67 | ||
| At least one | 12.1 | 107 | |||
| 2.0–2.99 | Head/neck/upper extremity | None | 12.3 | 65 | |
| At least one | 14.6 | 158 | |||
| Trunk/lower extremity | None | 17.3 | 75 | ||
| At least one | 23.7 | 177 | |||
| 3.0–4.0 | Head/neck/upper extremity | None | 10.0 | 30 | |
| At least one | 19.0 | 100 | |||
| Trunk/lower extremity | None | 20.0 | 35 | ||
| At least one | 22.1 | 104 | |||
| <75 | 1.01–1.49 | Head/neck/upper extremity | None | 7.5 | 199 |
| At least one | 10.1 | 208 | |||
| Trunk/lower extremity | None | 10.0 | 321 | ||
| At least one | 14.6 | 321 | |||
| 1.50–1.99 | Head/neck/upper extremity | None | 6.1 | 99 | |
| At least one | 8.7 | 127 | |||
| Trunk/lower extremity | None | 18.5 | 173 | ||
| At least one | 21.7 | 253 | |||
| 2.0–2.99 | Head/neck/upper extremity | None | 9.5 | 95 | |
| Trunk/lower extremity | |||||
| At least one | 16.4 | 195 | |||
| None | 24.4 | 156 | |||
| At least one | 28.4 | 331 | |||
| 3.0–4.0 | Head/neck/upper extremity | None | 17.1 | 41 | |
| Trunk/lower extremity | |||||
| At least one | 22.4 | 116 | |||
| None | 21.0 | 62 | |||
| At least one | 39.1 | 174 | |||
| ≥75 | 1.01–1.49 | Head/neck/upper extremity | None | 4.0 | 25 |
| Trunk/lower extremity | |||||
| At least one | 4.9 | 41 | |||
| None | 8.7 | 23 | |||
| At least one | 14.7 | 34 | |||
| 1.50–1.99 | Head/neck/upper extremity | None | 5.3 | 19 | |
| Trunk/lower extremity | |||||
| At least one | 13.9 | 36 | |||
| None | 0.0 | 18 | |||
| At least one | 12.9 | 31 | |||
| 2.0–2.99 | Head/neck/upper extremity | None | 17.9 | 28 | |
| Trunk/lower extremity | |||||
| At least one | 19.7 | 66 | |||
| None | 15.4 | 26 | |||
| At least one | 19.2 | 52 | |||
| 3.0–4.0 | Head/neck/upper extremity | None | 5.9 | 17 | |
| Trunk/lower extremity | |||||
| At least one | 20.0 | 45 | |||
| None | 28.6 | 14 | |||
| At least one | 9.5 | 42 |
Ulceration, lymphovascular invasion, mitotic rate ≥1, and/or microsatellitosis. Missing values for high-risk features were considered to be indicative of absence of the given high-risk feature.
4. Discussion
Our study of 3460 patients with intermediate thickness melanoma from centers across the United States had an overall positive sentinel lymph node biopsy rate of 17%, congruent with the 15% rate from the SEER database as reported by Kachare et al.6 Other large studies reported similar rates, though these were not confined to intermediate thickness lesions; 17% positive SLNB rate from the Melanoma Institute of Australia, 17% from the M.D. Anderson Cancer Center, and 17% from the Italian Multicenter Study.15,22,23 We identified age <60, location on the trunk or lower extremity, Breslow thickness ≥2 mm, and microsatellitosis as being independent predictors of having a positive SLNB in multivariate analysis. Age ≥60 was found to be protective of a positive SLNB. These findings are consistent with prior studies.14,24–27
Lesions located on the trunk or lower extremity were noted to be predictive of a positive SLNB. Callender et al. found an inverse relationship between melanoma thickness and risk for a positive SLNB based on the lesion location on the body.28 For instance, lesions on the head and neck had thicker melanomas, but a lower incidence of positive SLNB (5.1%) as compared to the thinner melanomas on the trunk but higher rate of positive SLNB. Further, Fadaki et al. have found that head and neck melanoma had the lowest SLN-positive rate at 10.8% (16.8% for extremity and 19.3% for trunk; p = .002) but had the worst 5-year DFS (p < .0001) and 5-year OS (p < .0001) as compared with other sites.29 Balch et al. similarly found trunk and lower extremity melanomas to be more likely associated with a positive SLNB compared to other sites.27,28 Our results showed similar variance of positive SLNB rates by lesion location to Balch et al. and Callender et al.
A statistical breakpoint for risk of SLNB positivity appears around age 60 and this has been reported previously in the Intergroup Melanoma Trial as well as the Sunbelt Melanoma Trial.30,31 Our study, as well as the Intergroup Melanoma Trial and Sunbelt Melanoma Trial have shown that older patients have a lower incidence of SLN positivity Our study did not evaluate survival but it has been previously demonstrated that age is an independent poor prognostic factor for survival in melanoma.32–34 Some authors have theorized this difference may result from the association of older patients with a higher incidence of acral lentiginous melanoma, desmoplastic melanoma, and head and neck melanomas associated with a lower incidence of nodal metastases.12,26,29 Despite this lower incidence of positive SLNB, older patients have worse prognosis for unclear reasons.34 This paradoxical relationship may be attributed to a tendency of melanoma in older patients for hematogenous rather than lymphatic spread.
There has been little debate regarding the recommendation for all patients with melanoma thicker than 1 mm to undergo a sentinel lymph node biopsy in the absence of clinically positive lymph nodes. Attempts to find low risk subgroups that may be spared SLNB in this intermediate subgroup have been pursued. Balch et al. performed a review of the AJCC database finding significant variance in rates of positive SLNB, inversely related regarding increasing age and deceasing rates of positive SLNB.
Bartlett et al. recently published subgroups of intermediate thickness melanoma that are at high risk for a positive sentinel node such as younger age, greater thickness, absent TIL, and present lymphovascular invasion or microsatellitosis. Additionally, they also described low risk groups with melanoma >1 mm in Breslow thickness. The authors identified 30% of their population (absent LVI, absent mitoses, and either absent regression or age of 60 and older) who may have a risk of a positive SLNB of less than 5%, suggesting that sentinel node biopsy could be omitted. Bartlett et al. identified two groups: patients with melanoma <1.5 mm Breslow thickness with absent mitoses, or with TIL present with absent regression (positive SLNB rate 2.6% and 4.3% respectively), or age of 60 and older without high risk features (no regression, present TIL, no ulceration, no LVI and no satellitosis), and tumors ≥1.5 mm Breslow thickness absent LVI, absent mitoses, absent regression or age of 60 and older (positive SLNB rate <5%). In our cohort, patients with melanoma <1.5 mm without stratification had a positive SLNB rate of 8.8% compared to 6.6% as published by Bartlett et al. Unfortunately in stratifying this group similarly (melanoma <1.5 mm thickness without high risk features) we found a higher positive SLNB rate of 7.1% (n = 224) compared to 2.6% (n = 38). In our patients with tumors ≥1.5 mm thickness in the absence of high risk features we found a positive SLNB rate of 16.0% (n = 748). Further stratifying these to patients older than 60 we still found a positive SLNB rate of 12.3% (n = 325), and were unable to reproduce the SLN positivity rate of <5% by Bartlett et al.
We were only able to find a small group of patients who fall into that less than 5% risk category such as demonstrated by the work by Bartlett et al.13 We found a number of subgroups with rates of positive SLNB less than 10%, however, only patients <60, with a Breslow thickness of 1.50–1.99, located on the head/neck/upper extremity and without any high-risk features had a positive SLNB rate of less than 5%, representing 1.9% of our study population (n = 65). 27.6% of patients (n = 936) had rates <10%: all low risk patients had a Breslow thickness of 1.01–1.99 mm. Searching for a larger group of patients at low risk for a positive SLNB, we then turned to our ≥75 year old cohort.
This cohort of older patients was stratified by thickness, tumor location, and presence or absence of high risk features (ulceration, lymphovascular invasion, mitotic rate ≥1, microsatellitosis). Patients older than or 75 years old with tumors 1.01–1.49 mm thickness on the head/neck/upper extremity with ≤1 high risk feature had a positive SLNB rate of 4.5% (n = 66). In this same ≥75 year old cohort patients with tumors 1.5–1.99 mm in thickness without high risk features regardless of location had a SLNB positivity rate of 2.7% (n = 37). If we use the acceptable threshold of 5% positive SLNB rate, then approximately 20% of patients (n = 103) in this population ≥75 years old (n = 517) could potentially be spared a sentinel lymph node biopsy. If we raise this threshold to a 10% positive SLNB rate, then 35.8% (n = 185) would fall beneath this positivity rate, again potentially sparing them an operation. However, overall we were unable to reproduce the low risk groups of positive SLNB as reported by Bartlett et al., and we did not find tumor infiltrating lymphocytes and absent tumor regression to be protective in our analysis.13,26
Our study was limited by factors inherent to retrospective, multi-institutional reports. All pathology was performed by institutional pathologists. Assessment of sentinel nodes was similar in performing multiple level sections and stained with hematoxylin and eosin, reflexing to immunohistochemistry if negative for metastases. One of the major limitations of the study is subgroup analysis and small numbers of patients in each subgroup, exemplified by the relatively broad confidence intervals associated with SLN positivity rates in our subgroups of patients ≥75 years of age. To verify this data or the data presented by Bartlett et al., a larger dataset needs to be analyzed to validate the findings.
5. Conclusions
Intermediate thickness melanoma is a heterogeneous group with varying risk of a positive sentinel lymph node biopsy. While the overall rate of a positive sentinel lymph node was 17%, various subgroups had substantially lower rates of positive SLNB. In particular, patients over the age of 60 had minimal increase in SLNB positivity from previously acknowledged high risk features (ulceration, lymphovascular invasion, mitotic rate ≥1, and/or microsatellitosis) and a lower overall sentinel lymph node biopsy positivity rate. An age cut off of 75 found groups of patients did have positive SLNB rates of less than 5% (19.9% of patients ≥75 years old) and who may avoid a sentinel lymph node biopsy. This may prove to be a clinically relevant subgroup for further clinical trials. In the ≥75 population, the likely low-risk for a positive sentinel lymph node must be weighed against the morbidity of the procedure and potential information to be gained. The decision to pursue a sentinel lymph node biopsy must be a decision between patient and provider based on the individual’s clinical situation and tumor characteristics which are more complex than just Breslow thickness and presence of mitosis or ulceration.
Acknowledgments
Funding
No discrete source.
Footnotes
Scientific Meeting Presentation: Society of Surgical Oncology 2016, Boston, MA, USA.
Commercial interests/disclosures
None.
References
- 1.Siegle RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7–30. doi: 10.3322/caac.21332. [DOI] [PubMed] [Google Scholar]
- 2.Morton DL, Thompson JF, Cochran AJ, et al. Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med. 2006 Sep 28;355(13):1307–1317. doi: 10.1056/NEJMoa060992. [DOI] [PubMed] [Google Scholar]
- 3.Balch CM, Cascinelli N. Sentinel-node biopsy in melanoma. N Engl J Med. 2006 Sep 28;355(13):1370–1371. doi: 10.1056/NEJMe068147. [DOI] [PubMed] [Google Scholar]
- 4.Reintgen D, Cruse CW, Wells K, et al. The orderly progression of melanoma nodal metastases. Ann Surg. 1994;220(6):759–767. doi: 10.1097/00000658-199412000-00009. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Essner R, Conforti A, Kelley MC, et al. Efficacy of lymphatic mapping, sentinel lymphadenectomy, and selective complete lymph node dissection as a therapeutic procedure for early-stage melanoma. Ann Surg Oncol. 1999;6(5):442–449. doi: 10.1007/s10434-999-0442-4. [DOI] [PubMed] [Google Scholar]
- 6.Kachare SD, Brinkley J, Wong JH, Vohra NA, Zervos EE, Fitzgerald TL. The influence of sentinel lymph node biopsy on survival for intermediate-thickness melanoma. Ann Surg Oncol. 2014 Dec 2013;:3377–3385. doi: 10.1245/s10434-014-3954-5. [DOI] [PubMed] [Google Scholar]
- 7.Han D, Thomas DC, Zager JS, Pockaj B, White RL, Leong SP. Clinical utilities and biological characteristics of melanoma sentinel lymph nodes. World J Clin Oncol. 2016;7(2):174–188. doi: 10.5306/wjco.v7.i2.174. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Karakousis GC, Gimotty PA, Czerniecki BJ, et al. Regional nodal metastatic disease is the strongest predictor of survival in patients with thin vertical growth phase melanomas: a case for SLN Staging biopsy in these patients. Ann Surg Oncol. 2007;14(5):1596–1603. doi: 10.1245/s10434-006-9319-y. [DOI] [PubMed] [Google Scholar]
- 9.Hieken TJ, Grotz TE, Comfere NI, Inselman JW, Habermann EB. The effect of the AJCC 7th edition change in T1 melanoma substaging on national utilization and outcomes of sentinel lymph node biopsy for thin melanoma. Melanoma Res. 2015;25(2):157–163. doi: 10.1097/CMR.0000000000000143. [DOI] [PubMed] [Google Scholar]
- 10.Turner RR, Essner R, Morton DL. Importance of sentinel lymph node biopsy in patients with thin melanoma. 2012;143(9):892–900. doi: 10.1001/archsurg.143.9.892. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Han D, Yu D, Zhao X, et al. Sentinel node biopsy is indicated for thin melanomas ≥0.76 mm. Ann Surg Oncol. 2012 Oct;19(11):3335–3342. doi: 10.1245/s10434-012-2469-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Han D, Zager JS, Shyr Y, et al. Clinicopathologic predictors of sentinel lymph node metastasis in thin melanoma. J Clin Oncol. 2013 Dec 10;31(35):4387–4393. doi: 10.1200/JCO.2013.50.1114. [DOI] [PubMed] [Google Scholar]
- 13.Bartlett EK, Peters MG, Blair A, et al. Identification of patients with intermediate thickness melanoma at low risk for sentinel lymph node positivity. Ann Surg Oncol. 2016 Jan;23(1):250–256. doi: 10.1245/s10434-015-4766-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.White RL, Ayers GD, Stell VH, et al. Factors predictive of the status of sentinel lymph nodes in melanoma patients from a large multicenter database. Ann Surg Oncol. 2011;18(13):3593–3600. doi: 10.1245/s10434-011-1826-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Testori A, De Salvo GL, Montesco MC, et al. Clinical considerations on sentinel node biopsy in melanoma from an Italian multicentric study on 1,313 patients (SOLISM-IMI) Ann Surg Oncol. 2009;16(7):2018–2027. doi: 10.1245/s10434-008-0273-8. [DOI] [PubMed] [Google Scholar]
- 16.Morton DL, Cochran AJ, Thompson JF, et al. Sentinel node biopsy for early-stage melanoma. Ann Surg. 2005;242(3):302–313. doi: 10.1097/01.sla.0000181092.50141.fa. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.McMasters KM, Noyes RD, Reintgen DS, et al. Lessons learned from the Sunbelt melanoma trial. J Surg Oncol. 2004;86(4):212–223. doi: 10.1002/jso.20084. [DOI] [PubMed] [Google Scholar]
- 18.Coit DG, Thompson JA, Andtbacka R, et al. Melanoma, version 4.2014. J Natl Compr Cancer Netw. 2014 May;12(5):621–629. doi: 10.6004/jnccn.2014.0066. [DOI] [PubMed] [Google Scholar]
- 19.McHugh JB, Su L, Griffith KA, et al. Significance of multiple lymphatic basin drainage in truncal melanoma patients undergoing sentinel lymph node biopsy. Ann Surg Oncol. 2006;13(9):1216–1223. doi: 10.1245/s10434-006-9014-z. [DOI] [PubMed] [Google Scholar]
- 20.Balch CM, Gershenwald JE, Soong SJ, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009;27(36):6199–6206. doi: 10.1200/JCO.2009.23.4799. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Lin HS, Watts JN, Peel NM, Hubbard RE. Frailty and post-operative outcomes in older surgical patients: a systematic review. BMC Geriatr. 2016;16(1):157. doi: 10.1186/s12877-016-0329-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Sassen S, Shaw HM, Colman MH, Scolyer RA, Thompson JF. The complex relationships between sentinel node positivity, patient age, and primary tumor desmoplasia: analysis of 2303 melanoma patients treated at a single center. Ann Surg Oncol. 2008;15(2):630–637. doi: 10.1245/s10434-007-9684-1. [DOI] [PubMed] [Google Scholar]
- 23.Rousseau DL, Ross MI, Johnson MM, et al. Revised American Joint Committee on Cancer staging criteria accurately predict sentinel lymph node positivity in clinically node-negative melanoma patients. Ann Surg Oncol. 2003;10(5):569–574. doi: 10.1245/aso.2003.09.016. [DOI] [PubMed] [Google Scholar]
- 24.Turaga K, Levine E, Barone R, et al. Consensus guidelines from the American Society of Peritoneal Surface Malignancies on standardizing the delivery of hyperthermic intraperitoneal chemotherapy (HIPEC) in colorectal cancer patients in the United States. Ann Surg Oncol. 2014 May;21(5):1501–1505. doi: 10.1245/s10434-013-3061-z. [DOI] [PubMed] [Google Scholar]
- 25.Leong SP, Accortt NA, Essner R, et al. Impact of sentinel node status and other risk factors on the clinical outcome of head and neck melanoma patients. Arch Otolaryngol Head Neck Surg. 2006;132(4):370–373. doi: 10.1001/archotol.132.4.370. [DOI] [PubMed] [Google Scholar]
- 26.Balch CM, Thompson JF, Gershenwald JE, et al. Age as a predictor of sentinel node metastasis among patients with localized melanoma: an inverse correlation of melanoma mortality and incidence of sentinel node metastasis among young and old patients. Ann Surg Oncol. 2014 Apr;21(4):1075–1081. doi: 10.1245/s10434-013-3464-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Balch CM, Gershenwald JE, Soong SJ, et al. Multivariate analysis of prognostic factors among 2,313 patients with stage III melanoma: comparison of nodal micrometastases versus macrometastases. J Clin Oncol. 2010;28(14):2452–2459. doi: 10.1200/JCO.2009.27.1627. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Callender GG, Egger ME, Burton AL, et al. Prognostic implications of anatomic location of primary cutaneous melanoma of 1 mm or thicker. Am J Surg. 2011;202(6):659–665. doi: 10.1016/j.amjsurg.2011.06.048. [DOI] [PubMed] [Google Scholar]
- 29.Fadaki N, Li R, Parrett B, et al. Is head and neck melanoma different from trunk and extremity melanomas with respect to sentinel lymph node status and clinical outcome? Ann Surg Oncol. 2013;20(9):3089–3097. doi: 10.1245/s10434-013-2977-7. [DOI] [PubMed] [Google Scholar]
- 30.Balch CM, Soong S, Ross MI, et al. Long-term results of a multi-institutional randomized trial comparing prognostic factors and surgical results for intermediate thickness melanomas (1.0 to 4.0 mm). Intergroup Melanoma Surgical Trial. Ann Surg Oncol. 2000;7(2):87–97. doi: 10.1007/s10434-000-0087-9. [DOI] [PubMed] [Google Scholar]
- 31.McMasters K, Wong S, Edwards M, et al. Factors that predict the presence of sentinel lymph node metastasis in patients with melanoma. Surgery. 2001;130:151–156. doi: 10.1067/msy.2001.115830. [DOI] [PubMed] [Google Scholar]
- 32.Balch CM, Soong S, Gershenwald JE, et al. Prognostic factors analysis of 17, 600 melanoma patients: melanoma staging system. Society. 2001;19(16):3622–3634. doi: 10.1200/JCO.2001.19.16.3622. [DOI] [PubMed] [Google Scholar]
- 33.Macdonald JB, Dueck AC, Gray RJ, et al. Malignant melanoma in the elderly: different regional disease and poorer prognosis. J Cancer. 2011;2(1):538–543. doi: 10.7150/jca.2.538. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Cavanaugh-Hussey MW, Mu EW, Kang S, Balch CM, Wang T. Older age is associated with a higher incidence of melanoma death but a lower incidence of sentinel lymph node metastasis in the SEER databases (2003–2011) Ann Surg Oncol. 2015;22(7):2120–2126. doi: 10.1245/s10434-015-4538-8. [DOI] [PubMed] [Google Scholar]