Abstract
Background/Aim: The frequency of brain metastasis (BM) is up to 45-50% in patients with advanced melanoma. Our aim was to identify the risk factors for the early occurrence of BM. Patients and Methods: A total of 333 patients with BM were identified from our database of 2,972 patients with melanoma between 2003-2015. Results: The median elapsed time to BM (TTBM) was significantly associated with Breslow thickness, ulceration, location, and patient age. Head and neck location was the strongest predictor for early BM development [hazard ratio (HR)=1.81, 95% confidence interval (CI)=1.05-3.12; p=0.031) followed by Breslow thickness >2 mm (HR=1.53, 95% CI=1.04-2.23; p=0.027). Body part-specific median TTBM was 51.5, 43, 38.5, 32, 35, 36.5, 35.5 and 19 months in leg-foot, thigh, abdomen-pelvic, chest-back, lower arm-hand, upper arm-shoulder, face-neck and scalp regions, respectively. Conclusion: We suggest brain magnetic resonance imaging follow-up in the high-risk patient group of patients with melanoma in the head and neck region, especially for those with primary melanoma over Breslow 2 mm located in the scalp.
Brain metastases (BM) are frequent in stage IV malignant melanoma: brain involvement has increased to 45-50% in those having advanced melanoma (1) and 75% at autopsy (2). Even with the use of new targeted and immune therapies, BM is still the most important factor as it determines quality of life and life expectancy. However, in cases of early detection, the results are promising. Regarding the new therapeutic possibilities, early detection has an increasing role in managing patients with melanoma with BM. Therefore, the aim of this retrospective study was to identify risk factors useful in predicting the early development of BM and to highlight the strongest ones in order to determine a high-risk patient group.
Patients and Methods
From our melanoma database of 2,972 patients between 2003 and 2015, we identified 333 diagnosed with BM. One group of these patients was treated at our Center from the discovery of their primary melanoma, the other was referred to us after the development of BM for complex oncotherapy, including stereotactic radiosurgery. The following parameters were registered: gender, age at diagnosis (tested in categories per 10 years), location of the primary melanoma [head and neck (HN), trunk, upper extremity and lower extremity], Breslow thickness (investigated in two categories of <2.0 mm and ≥2.0 mm), ulceration (presence or absence), histological subtype (nodular, superficial spreading, acral lentiginous or lentigo maligna melanoma) and sentinel lymph node (SLN) status (positive for metastasis or negative). SLN biopsy was performed mostly in cases of intermediate tumor thickness excluding the HN region, according to our institutional protocol from 1999.
We analyzed these parameters in association with the median elapsed time to brain metastasis (TTBM). TTBM was calculated from the date of primary tumor diagnosis to the detection date of BM. With those factors showing significant correlation with TTBM, further analysis was carried out to compare their predictive value. Finally, we investigated the distance-based associations by distributing the primary site regions into smaller categories and then determining TTBM for each.
Statistical methods. After having described the whole study population, we excluded patients with melanoma whose primary was unknown. For TTBM analysis, patients whose primary melanoma was not removed before they first presented with BM were also excluded. In order to compare the primary site to brain distances objectively along a straight axis, there was further exclusion of patients with upper limb melanoma. For mapping all distance-related associations, we analyzed every region again.
The effect of the variables on early BM occurrence was determined by univariate Cox regression analysis, and the combined effect of these predictors was assessed by using multivariate Cox regression analysis. The significance of the models was evaluated by the log-rank test and results with two-sided p<0.05 were considered significant. All analysis was performed in R statistical software (R Foundation for Statistical Computing, Vienna, Austria; version 3.0.3.) using the survival package in R. Kaplan–Meier curves, were plotted using the survMisc package in R.
Results
A total of 333 patients with melanoma were included in our analysis, who developed BM during the study period (2003-2015). Patient characteristics are shown in Table I. The median Breslow thickness was 3.0 mm (mean=4.13 mm, range=0.1-40 mm), 173 patients (69.5%) fell in the ≥2 mm and 76 patients (30.5%) into the <2 mm groups.
The median TTBM for the whole patient group was 36 months (range=0.5-305 months). Potential risk factors were analyzed in association with TTBM, starting with the location of the primary melanoma. The median TTBM was 32 months for primary of the HN region, 34.5 months for those of the trunk, while it was much longer, 51.5 months, for those of the lower limb region (Figure 1). Compared with melanoma located in the lower limb, location in the trunk conferred a significantly higher risk of shorter TTBM [hazard ratio (HR)=1.4, 95% confidence interval (CI)=1.01-1.94; p=0.046;N=190], and the HN location conferred even greater increased risk for early onset of BM (HR=2.18, 95% CI=1.44-3.32; p=0.00026; N=95). Detailed analysis of the primary location (Figure 2) showed that the median TTBM was 51.5 months when melanoma started in the leg-foot region (n=36, 13%), 43 months if disseminated from the thigh (n=12, 4%), 38.5 months from the abdomen-pelvic region (n=38, 14%), 32 months from the chest-back region (n=79, 29%), 35 months from the lower arm-hand region (n=8, 3%), 36.5 months from the upper arm-shoulder (n=54, 20%), 35.5 months from the face and neck (n=24, 9%), and was only 19 months for those originating in the scalp region (n=22, 8%). In this respect, scalp location was sharply separated from the other parts of the HN (HR=1.84, 95% CI=1.01-3.34; p=0.047) and showed outstanding risk for BM compared to those arising from the leg-foot region (HR=3.03, 95% CI=1.76-5.22; p=0.000063). The face-neck region was also a significant risk factor compared with the leg-foot regime (HR=1.75, CI=1.03-2.96; p=0.038).
In the group with Breslow thickness ≥2 mm, the median TTBM was 31 months, while for those with <2 mm it was 47.5 months (HR=1.37, 95% CI=1.05-1.8; p=0.023; n=249). In cases of ulceration, the median TTBM was 26.5 months, while in the non-ulcerated group it was 43 months (HR=1.58, CI=1.17-2.13; p=0.0025; n=195). As for age, we found that older age elevated the risk of short TTBM (per 10-year increase: HR=1.19, CI=1.09-1.31; p=0.00014; n=272).
TTBM was significantly correlated with patient age, the primary location (either as a single variant, by log-rank test p=0.001), the Breslow thickness and the presence of ulceration (as previously detailed). We found no significant association between TTBM and gender (p=0.17), histological subtype (p=0.53) or SLN status (p=0.30).
Characteristics of the melanoma study population.
We carried out further analysis with the significant independent risk factors using a multivariate Cox regression model including age, location, tumor thickness and ulceration to evaluate their predictive strength for TTBM. As a reference point of the comparison, we took a hypothetical low-risk group of young patients with thin (<2 mm) primary melanomas located on the lower extremity, without ulceration, and then the joint effect of the studied predictors (six variables: age, location of HN, of upper limb and of trunk, Breslow of ≥2 mm, and presence of ulceration) was compared to this group. Our results showed that HN location (HR=1.81, 95% CI=1.05-3.12; p=0.031) and Breslow thickness ≥2 mm (HR=1.53, 95% CI=1.04-2.23; p=0.027) remained statistically significant out of six variables, and the HN location was the strongest predictor among all, followed by Breslow tumor thickness (Figure 3). When Breslow thickness was neglected in this calculation, ulceration became significant, and the second strongest factor after HN location. The association between tumor thickness and ulceration may explain this finding.
Kaplan–Meier curves of distance-based time to brain metastasis (TTBM). The risk of early brain metastasis significantly drops in the following order of primary tumor location: head and neck, trunk, and lower extremity.
Detailed subdivision of primary tumor location and time to brain metastasis (TTBM). TTBM tends to gradually decrease with proximity to the scalp. Note that scalp location is sharply demarcated from other head and neck regions.
Discussion
BM development is a frequent complication of malignant melanoma. The prognosis depends on the staging categories of M1a, M1b, M1c, even in disseminated phase. By the time any dissemination is diagnosed, BM can already be detected in 20% of all cases (3). Early detection can prolong survival because of better surgical and radiosurgical options for fewer and smaller lesions. The median overall survival time after developing BM is generally 4 months, but radiosurgery can result in 6.6 months, which might be even improved to 12.5 months by combining it with surgical resection in selected population (4). For patients with stable BM, more favorable results are expected with the possibility of new therapies. Targeted and immunotherapies statistically improved survival in clinical studies, even in cases of cerebral progression. Median overall survival reached 33 weeks with dabrafenib (4) and 7 months with ipilimumab in cases of asymptomatic BM (5), while nivolumab and pembrolizumab are currently being explored in several ongoing trials in patients with BM from melanoma (5). Early detection of BM and the use of new therapies would maximize the chance for the best survival.
Relative risk associated with the main variables for early onset of brain metastasis from melanoma. Head and neck location is the strongest predictor for early onset, followed by greater Breslow tumor thickness. HR: Hazard ratio; CI: confidence interval.
There have been several prior studies aimed at finding BM predictors in patients with melanoma. In these studies, Breslow thickness and ulceration were reported to be the major risk factors, while certain studies added HN location, age, gender, SLN status and histological melanoma subtype to prior predictors (6-8). The predictive strength of these variables is controversial, but some authors suggest that location and ulceration are the strongest ones, consequently patients with primary ulcerated melanoma on the head and neck might be at higher risk for development of BM (9). Moreover, within the HN region, primary scalp melanomas were recently reported to be associated with a higher incidence of BM than face or neck melanoma (10).
Our study includes a large dataset of patients with melanoma with BM compared to prior studies, where the number of the BM population mostly remained under 150 patients. The demographic and clinicopathological features of the current analysis were mostly similar to previously published data. Our patients' mean Breslow thickness of 4.13 mm and the ulceration rate of 58% corresponded to Bottoni et al.'s mean tumor thickness of 4.0 mm (8) and approached the results of Timothy et al., as they found a mean Breslow thickness of 3.4 mm and an ulceration rate of 55% for their BM population (6), but surprisingly differed from the 1.85 mm tumor thickness and 48% ulceration of Zakrzewski et al. (9). Since our study population selectively included patients with brain metastases, we analyzed the variables in accordance with the TTBM, while other studies mostly calculated BM frequency; thereby we identified the predictors of early BM onset instead of predictors of BM incidence. Our collected TTBM data of 36 months is longer than those of the literature data [23-30.5 months (7-9)], but if by not excluding cases with unknown primaries, we obtained 28 months as the TTBM that is similar to the results of these studies.
TTBM was significantly correlated with older age, HN location of the primary tumor, greater Breslow depth and the presence of ulceration, consistent with prior studies. However, we found no significant association between TTBM and gender, histological subtype or SLN status, contrary to certain reports where male gender (10-11), acral lentiginous and nodular primary tumor (12), or positive SLN (8) were concluded as risk factors for BM. Even with our 28% sentinel positivity rate, which is higher than literature data of 23.8% (8), and our previously reported data of 14.7% (13), there was no significance regarding TTBM.
We observed that the distance between the primary melanoma site and the brain strongly affected TTBM. Accordingly, we analyzed our data in a distance-based manner instead of the usual axial (HN, trunk) versus peripheral (limbs) site distribution, although axial location of primary melanoma is widely considered to be more likely to develop BM than peripheral. Our results demonstrated that the risk of early BM was higher in HN than trunk-located melanoma, which was at higher risk than location in the lower extremity. The large number of patients in the current analysis enabled us to perform more specific subdivision of regions regarding the anatomical site of the primary tumor. In this way, the scalp location resulted in a TTBM of 19 months, hence sharply demarcated from other HN regions. This face and neck region falls under the standard category of the trunk and upper extremity level, with TTBM in the range of 32-38.5 months. As a next lower segment, the thighs were associated with a median TTBM of 43 months, while the lowest segment including legs and feet had the longest, 51.5 months median TTBM. Consequently, a distance-based subdivision appears to be preferable instead of axial versus peripheral distribution.
Conclusion
Our study revealed that the HN region, and especially location in the scalp, was the strongest predictor for BM onset among all factors, the second prognostic factor was a Breslow thickness >2 mm, followed by the presence of ulceration and older age respectively. Based on these findings, we identified a high-risk group of patients for BM with HN (scalp) located primary melanoma greater than Breslow thickness of 2 mm. For this well-circumscribed relatively small subpopulation, we suggest a closer evaluation using brain MRI which has not generally been part of routine follow-up protocols in clinical practice. In this way, BM would be discovered at an earlier stage and could be treated more effectively, particularly when in possession of new therapies.
Acknowledgements
This study was supported by the Hungarian government (KTIA_NAP 13-1-2013-0001). Parts of these results were presented as a poster at the European Society for Medical Oncology Conference 2015 in Vienna.
- Received April 5, 2016.
- Revision received April 29, 2016.
- Accepted May 11, 2016.
- Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
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