Prognostic value of sentinel lymph node biopsy in melanomas of different Breslow ’ s thickness

BACKGROUND: Although sentinel lymph node biopsy (SLNB) is the most sensitive and accurate investigative modality for establishing regional node status in patients with melanoma, its role and benefit in melanoma of different Breslow’s thickness is still controversial. OBJECTIVE: The current study aimed mainly to evaluate the effects of SLNB results on important outcome parameters in primary melanomas with different Breslow’s thicknesses. METHODS: In a retrospective cohort (1990 to 2014), all cases of single, primary localised cutaneous melanoma tumours were evaluated. Data collected consisted of tumour location, tumour type, ulceration, Breslow’s thickness and SLNB result. In addition, locoregional recurrence, distant metastases, disease-free and overall survival were used as the important parameters to compare outcome among the various groups in the current study. RESULTS: A total of 1111 patients (527 female, 584 male; mean age 64.33 ± 15.44 years) were considered in the analyses in this study, with mean follow-up of 22 77.3 days. The multivariate Cox analysis showed that age, ulceration, Breslow’s depth and SLNB result significantly decreased disease-free survival. This analysis also demonstrated that age, gender, ulceration, Breslow’s depth and SLNB result significantly affected overall survival. Furthermore, the Kaplan-Meier method showed that the patients with negative SLNB had longer disease-free survival than the patients with positive SLNB in thin, intermediate and thick melanomas (p <0.001, p <0.001 and p = 0.008, respectively). Additionally, in the patients with intermediate melanomas significant better overall survival outcome was observed in those with negative SLNB (p <0.001). Despite worse mean overall survival of the patients with thin or thick melanomas and positive SLNB compared with the patients with negative SLNB, this difference was not statistically significant (p = 0.077 and p = 0.13, respectively). CONCLUSION: Sentinel lymph node biopsy of melanomas provides important prognostic information and the outcome provides additional information for the management and treatment of the patient.


Introduction
Malignant melanoma is a common type of skin cancer, which is potentially lethal if not diagnosed and excised at an early stage [1][2][3].Although mortality rates have increased at a significantly lower rate, which has been attributed to improved early detection as evidenced by the diagnosis of thinner lesions over this time period [4,5], its incidence continues to increase fastest of all cancers in Switzerland [6].Since there is such a high incidence rate of melanoma, population-based data are important to improve early diagnosis and streamline screening programmes in local populations [3].It is estimated that approximately 15 to 25% of patients with a clinically negative lymph node examination carry microscopic nodal metastases.As a result, sentinel lymph node biopsy (SLNB), which is the most sensitive and accurate investigative method for establishing regional node status in patients with melanoma, has gained rapid acceptance in the treatment of patients with melanoma [7][8][9][10][11].However, its role and benefit in patients with melanomas of different Breslow's thickness is still controversial [12].As a result, the current study mainly aimed to evaluate the effect of lymph node biopsy results on diseasefree and overall survival of patients with melanomas of different Breslow's thickness.

Materials and methods
We performed a retrospective cohort review of the melanoma database of patients from the University Hospital Bern, Switzerland.The study period was from 1990 to 2014, with the follow-up ending in 2015.All cases of single, primary localised cutaneous melanoma tumours were evaluated.Patients without complete medical records, documented surgical margins or regular follow-up were excluded from the study.All procedures were carried out in accordance with the standards of the ethical committee of the Canton of Bern, Switzerland (2016-00382), on human experimentation and with the Helsinki Declaration of 1975, as revised in 1983.Collected data consisted of patients' gender, age, tumour location, tumour type, Breslow's thickness, ulceration and SLNB result.In addition, locoregional recurrence, distant metastases, disease-free and overall survival were used as the crucial parameters to compare outcome between the study groups.In this study, the lesions were categorised into thin (≤1.0 mm), Intermediate (1.0-4.0 mm) and thick melanomas (≥4.0 mm) [13].Additionally, locoregional recurrence after primary excision was considered to include recurrence locally at the site of the primary lesion, regionally in the draining lymph node basin, and/or anywhere in between [11,[14][15][16].Spread from primary tumour to distant lymph nodes or distant organs was defined as distant metastasis [17][18][19].

Statistical analysis
All analyses were conducted using SPSS version 21.0 (IBM, Armonk, NY, U.S.A.).All p-values relate to a twosided test with an α level of 0.05.For categorical and continuous characteristics, χ 2 -test, Fisher's exact test and analysis of variance (ANOVA) were used to detect possible differences among the study groups.Disease-free and overall survival were estimated using the Kaplan-Meier method.For disease-free survival, patients confirmed to be without locoregional recurrence or distant metastasis were censored using their last contact date.For overall survival, patients confirmed to be alive were censored using their last contact date.The confidence interval (CI) of hazard ratios (HRs) for Cox regression and overall survival (for time-to-event variables) were calculated.The p-value based on log rank (Mantel-Cox test) was used to check if the study groups had different disease-free and overall survival functions.The Cox proportional hazard model was used to estimate the bivariate association between each endpoint and the available patient/tumour characteristics.Prognostic factors considered for the multivariate Cox analysis of the primary melanomas were age, gender, tumour thickness, ulceration and positive SLNB [9, 20,21].A p-value<0.05 was considered statistically significant.

Patient and tumour characteristics
Between 1990 and 2014, 1111 patients (527 female, 584 male; mean age 64.33 ± 15.44 years) with single, primary localised cutaneous melanoma tumours were considered in the analyses in this study, with mean follow-up of 22 77.3 days.The mean ± standard deviation (SD) Breslow's depth of the study patients' primary melanoma tumours was 1.92 ± 2.70 mm (0.09-45 mm).A total of 179 (16.1%) of our study patients had ulceration in their tumours.Superficial spreading melanoma was the most frequent (48.6%) and amelanotic melanoma the least frequent (0.5%) tumour type.Furthermore, the trunk area was the location of the highest number of primary tumours (40.0%).For 889 (80.0%) patients, SLNB was performed.Of the melanomas evaluated, 464 (41.8%) were thin, 523 (47.0%) intermediate and 124 (11.2%) thick.As presented in table 1, statistical analysis showed no significant differences between the patients in the different thickness groups regarding age, gender and melanoma location.However, the incidence of ulceration, positive sentinel lymph node biopsies, metastasis and death increased significantly with the thick melanomas (p <0.001).Furthermore, the multivariate Cox analysis showed that age, ulceration, Breslow's depth and SLNB result significantly influenced disease-free survival.This analysis also showed that age, gender, ulceration, Breslow's depth and SLNB result significantly affected overall survival (table 2).

The prognostic value of sentinel lymph node biopsy in patients with thin melanomas
Ten (2.2%) patients with thin melanoma had locoregional recurrence and 15 (3.2%) had distant metastases, which were significantly more frequent in the patients with positive SLNB (p = 0.007 and p = 0.003; respectively).However, although the death attributed to melanoma was more frequent in the patients with positive SLNB, this difference was not statistically significant (p = 0.187; tables 1 and 3).Furthermore, Kaplan-Meier methods showed that the patients with negative SLNB had better disease-free survival than the patients with positive SLNB (p<0.001).Although mean overall survival time of the patients with positive SLNB (11.92 years, 95% CI 10.14-13.71)was less than in the patients with negative SLNB (23.45 years, 95% CI 23.06-23.84),this difference was not significant (p = 0. 077; table 4, fig.1).

The prognostic value of sentinel lymph node biopsy in patients with intermediate melanomas
Locoregional recurrence, distant metastases and death attributed to melanoma occurred in 74 (14.1%), 69 (13.2%)

Original article
Swiss Med Wkly.2016;146:w14358 and 51 (9.8%), respectively, among the patients with intermediate melanomas, and were significantly more frequent in the patient with positive SLNB (p <0.001; tables 1 and 3).Additionally, Kaplan-Meier survival analysis showed significantly better disease-free and overall survival in the patients with negative SLNB than in the patients with positive SLNB (p <0.001; table 4, fig.2).

The prognostic value of sentinel lymph node biopsy in patients with thick melanomas
Evaluation of thick melanomas showed 41 (33.1%) patients with locoregional recurrence, 41 (33.1%) with distant metastases and 29 (23.4%) with death attributed to melanoma, which were significantly more frequent in the patients with positive SLNB (p = 0.001, 0.017 and 0.05; respect- Effect of sentinel lymph node biopsy (SLNBx) result on disease-free and overall survival in thick melanoma (p = 0.008 and p = 0.13, respectively).

Discussion
The use of SLNB for accurate disease staging is a key part of the early detection of occult metastatic disease in the regional lymph nodes and the preliminary management of many people with localised melanoma [22][23][24][25].However, it is not uniformly accepted at all specialised centres as the standard of care as a result of the important controversy relating to its usefulness (therapeutic efficacy, safety and costs) [22,25].However, our study on different melanoma groups indicated that a positive SLNB is associated with worse outcomes in melanoma patients, regardless of melanoma thickness.In this study, multivariate Cox analysis found that age, ulceration, Breslow's depth and SLNB result significantly decreased disease-free survival.Others have also reported the impact of SLNB status [12, [26][27][28], ulceration [12,26,27], and increased Breslow's thickness [12,28,29] on disease-free survival.This analysis also demonstrated that age, gender, ulceration, Breslow's depth

Thin melanoma
The overall incidence of a positive SLNB in thin melanoma in prior studies has ranged from 0 to 7.8% but the studies differed in their definition of thin melanoma and inclusion criteria [25,[30][31][32][33][34][35].Similarly, positive SLNB was detected in 5.0% of our patients.Some authors have suggested that SLNB is not useful unless it can be shown to improve survival, because thin primary melanoma has a 96% survival rate after 20 years of follow-up [36,37].However, other authors demonstrated sentinel node metastases as the single most important prognostic indicator in patients with melanoma [36,38,39].Of the patients with thin melanoma, 10 (2.2%) with locoregional recurrence and 15 (3.2%) with distant metastases were observed, and there were significantly more among the patients with positive SLNB (p = 0.007 and p = 0.003, respectively).Furthermore, Kaplan-Meier methods interestingly showed that the patients with negative SLNB had better disease-free survival than the patients with positive SLNB (p <0.001).
Our findings provide support for previous analyses [25,39,40], which showed that disease-free survival is significantly associated with SLNB results in patients with thin melanomas.Nevertheless, Wong et al. [41] did not find a significant difference between thin melanomas with positive and negative sentinel lymph nodes regarding diseasespecific survival (p = 0.77).Although mean overall survival time in the patients with positive SLNB was less than the patients with negative SLNB, this difference was not statistically significant (p = 0.077) in our study.However, in the recent studies, the importance of sentinel node status in overall survival of melanoma patients was supported, since thin melanomas with positive SLNB had significantly poorer prognosis [25,39,40,42].

Intermediate melanoma
The  [43], which might be due to the thicker mean Breslow's depth in their groups compared with our patients (1.98 ± 0.63 mm vs 1.92 ± 2.70 mm).A significant difference between sentinel node negative and node positive groups was also observed in our study for disease-free and overall survival (p <0.001).This observation is consistent with prior reports of intermediate melanoma patients by Morton et al., which showed significantly shorter disease-free and overall survival in their patients with intermediate melanomas if the sentinel node was free of metastases (p <0.001) [43].

Limitations
Our current study is certainly not without limitations.The chief of them was the study design -a retrospective observational study -and all the biases associated with this kind of study should be taken into consideration.Furthermore, we were not able to assess concerns about the morbidities and complication rates following SLNB for our melanoma patients.

Conclusion
The information obtained from the present study provides insight into application of SLNB as a prognostic indicator in patients with different thicknesses of melanoma.Based on a recent phase III trial conducted by Morton et al. [38], performing SLNB per se might not significantly change 10-year melanoma-specific survival, but it can significantly prolong 10-year disease-free survival compared with an observation group.Furthermore, biopsy-based staging of melanomas provides important prognostic information, and its outcome will inform the next steps in patient management, as it identifies patients with nodal metastases who might benefit from immediate complete lymphadenectomy or use of potential adjuvant therapies [38,42,55,56].

Figures (large format)
Effect of sentinel lymph node biopsy (SLNBx) result on disease-free and overall survival in thin melanoma (p <0.001 and p = 0.077, respectively).Effect of sentinel lymph node biopsy (SLNBx) result on disease-free and overall survival in thick melanoma (p = 0.008 and p = 0.13, respectively).

Figure 1
Figure 1Effect of sentinel lymph node biopsy (SLNBx) result on disease-free and overall survival in thin melanoma (p <0.001 and p = 0.077, respectively).

Figure 2
Figure 2Effect of sentinel lymph node biopsy (SLNBx) result on disease-free and overall survival in intermediate melanoma (p <0.001 and p <0.001, respectively).

Figure 2
Figure 2 Effect of sentinel lymph node biopsy (SLNBx) result on disease-free and overall survival in intermediate melanoma (p <0.001 and p <0.001, respectively).

Table 1 :
Patients and tumour characteristics according to melanoma thickness.

Table 2 :
Cox analysis based on melanoma thickness.
CI = confidence interval; SLNB = sentinel lymph node biopsy Original article Swiss Med Wkly.2016;146:w14358 Swiss Medical Weekly • PDF of the online version • www.smw.ch [43]dence of a positive SLNB in the intermediate melanoma group in the current study was 19.3%.However, Morton et al. found 16.0% tumour-positive sentinel nodes in intermediate melanomas[43].

Table 3 :
The association between sentinel lymph node biopsy result and clinical outcomes in patients with melanomas of different thickness.

Table 4 :
The association between sentinel lymph node biopsy (SLNB) result and clinical outcomes in patients with different melanoma thicknesses.
Disclosure statement: No financial support and no other potential conflict of interest relevant to this article was reported.Correspondence: S. Morteza Seyed Jafari, M.D., Department of Dermatology, University Hospital, Inselspital, University of Bern, CH-Bern 3010, seyedjafarism[at]yahoo.com