The probability for recurrence-free survival after 5 years was 13.8% overall 3 groups, 8.1% with mucosal melanoma in the head/neck region, and 23.8% in the FGT, a 5-year follow-up period was not reached for anorectal tumors (Fig. 1A). Again a significant advantage could be demonstrated for the group with melanomas in the FGT for the recurrence-free survival versus the patients with anorectal and head/neck tumors (P = 0.03, Table 2).
For patients under 60 years of age at the time of 1st diagnosis we saw a trend for an advantage in overall and recurrence-free survival (P = 0.06, Table 2, Fig. 1E).
Patients in disease stage I at the time of 1st diagnosis had significant advantage in terms of overall survival (P = 0.04, Fig. 1D, Table 2) and a highly significant for the recurrence-free survival (P < 0.001, Table 2) in comparison with patients with stages II and III at the time of the initial diagnosis.
In regard to gender no significance for overall and recurrence-free survival could be demonstrated.
Because of the long period of observation we divided the patients in 3 groups, 1993 to 2005, 2006 to 2009, and 2010 to 2015, the comparison showed no significant difference between the groups for recurrence-free survival and overall survival (Fig. 1F).
In the group of head/neck mucosal melanomas, in which the major part of the adjuvant radiation took place, a significant advantage (P = 0.02) toward the prevention of local recurrences was shown (Fig. 2).
As expected the multivariate analysis (Table 3) showed a high statistical significance for the tumor-stage at time of the initial diagnosis in terms of recurrence-free survival (P < 0.001). Also age younger than 60 was correlated with a significant recurrence-free survival benefit (P = 0.03). In contrast the localization of the primary did not reach any independent prognostic significance.
3.4 KIT/BRAF mutations
A molecular analysis of the KIT-gene was performed in 62 of the patients studied. A total of 7/62 (11.3%) of the patients had a KIT mutation, 5 in exon 11 (once each 579del, K550N, W557R, twice L576P), 1 in exon 13 (K642E), and 1 in exon 18 of the KIT-gene (I841V). The analysis for 36 patients was done in our own laboratory (exons 9, 11, 13, 17, and 18), 6 of them showed a KIT-mutation. These results were already described in detail. Within the TEAM-study (Tasigna Efficacy in Advanced Melanoma) the KIT-exons 9, 11, 13, and 17 were analyzed in 6 further patients, all 6 patients did not show a mutation. Another 20 analyses were done during routine diagnostics employing Sanger-Sequencing of the exons 9, 11, and 13, which revealed a K642E-mutation in 1 patient. In regard to localization of the primary tumor KIT-mutations were shown in 2/27 (7.4%) patients in the head/neck region, 2/16 (12.5%) anorectal, and 3/19 (15.8%) in the FGT.
A BRAF V600E Mutation was demonstrated in 2/57 (3.5%) of the patients, one each in the anorectal and head/neck-group.
3.5 Targeted therapy and therapy with checkpoint inhibitors
Four patients were treated with targeted therapies, patients 1 to 3 with imatinib due to a KIT-mutation in exon 11 or 13. Patient 1 achieved a short-term partial remission (PR), patient 2 a short-term stable disease (SD) (Table 4).
Patient 4 (Table 4) is a male patient with a metastasized anorectal melanoma harboring a BRAF mutation. Therapy with ipilimumab yielded in a PR for 6 month, subsequent vemurafenib-therapy resulted in a PR for another 5 month. Reexposition first with ipilimumab then with vemurafenib did not lead to any further tumor control.
Besides these patients 6 other patients were treated with ipilimumab (Table 4), one of those had an SD for 4.5 months. Seven patients received programmed disease-1 (PD-1)-checkpoint inhibitors (Table 4), in 2 patients a PR lasting 366+ and 240+ days was achieved.
Mucosal melanoma is disease of advanced age, among our patients the median age over all 3 groups was 66 years corresponding well to the spectrum described in the literature ranging from 60 to 75 years.[8,13–17]
The gender distribution with 57% female patients was consistent with other observations and can be explained by the patients with melanoma in the FGT.[15,18] As described in the literature male patients suffered more often (69%) from mucosal melanomas in the head/neck region. Anorectal melanomas showed a fairly balanced gender distribution with 53% male patients in our study in contrast to the literature where mostly a higher ratio of male patients is described.[16,19]
An SLN biopsy is particularly possible if lymph drainage into peripheral lymph stations is expected, for example, distal the linea dentata for anal melanomas or vulvar melanomas in the FGT. In individual cases SLN biopsy is described even for mucosal melanomas in the head/neck region. Contrary to cutaneous melanomas the SLN is not established as a prognostic factor in mucosal melanoma. For having a poor prognosis in respect of distant metastasis a complete regional lymph node dissection following a positive SLN is discussed controversially.[20,21]
During follow-up 79% of the patients had a recurrence, especially mucosal melanomas in the head/neck region demonstrated a short recurrence-free survival time with a median of 10 months. In our study 64% of the patients died during follow-up, the 5-year survival rate was 26.3%, which is slightly lower than indicated in the literature with 5-year survival rates of 32.4%, 34%, and up to 55.8%.
In line with expectations, the tumor-grade is an important prognostic factor as described in the literature.[17,22]
In our study, the age with a threshold value of 60 years was an additional important prognostic factor. In the literature age is described as a prognostic factor for either mucosal melanomas[14,22] and skin melanomas.
A better prognosis for tumors in the FGT became apparent in our univariate analysis but could not be confirmed in the multivariate analysis. Mehra et al could also show a better prognosis for vulvar melanomas in comparison to other localizations of the primary tumor.
Local recurrence occurred notably in patients with the primary tumor in the head/neck region, which had not undergone adjuvant radiotherapy, among the adjuvant group the local tumor control was significantly better.
Some studies already have shown that adjuvant radiation of mucosal melanomas in the head/neck region can reduce the risk of local recurrence from 33%–83% to 0%–56%. Another study could demonstrate that at least 54 Gray should be applied to have a positive effect.
For KIT-mutations we could show a higher rate in mucosal melanomas in the FGT (15.8%) in comparison to the other 2 groups, head/neck (7.4%) and anorectal (12.5%). This is consistent with a recent publication that outlined the highest rate of KIT-mutations for vulvovaginal melanomas (35%) followed by anorectal melanomas (25%) and mucosal melanomas in the head/neck region (10%).
In our patient collection, the treatment with imatinib showed 1 short-term SD and 1 short-term PR in 2 of 3 patients with KIT-mutations in exon 11 and 13, respectively (Table 4).
In the literature, several case series describe an objective response in 16% to 30% of the patients treated imatinib, the median time for recurrence-free survival was about 3 months, with major benefit for patients with mutations in exon 11 and 13.[27–29]
In a case series with 7 patients with mucosal melanomas and KIT-mutations in exon 11 or 13 sunitinib showed a response in 3 cases.
A reason for the relative poor response to KIT-inhibitors could be a concurrent NRAS-mutation, which are described in patients with KIT-mutations. This results in activation of the pathway downstream of KIT, thus it is advisable to rule out NRAS-mutations before using a KIT-inhibitor.
BRAF-mutations are described in mucosal melanoma. In our cohort 3.5% of the patients examined displayed a BRAF-mutation, in the literature the values differ from 3.6%, 6% up to 11.1%, and 16.5%. Little is published on the response of targeted therapies in BRAF positive patients with mucosal melanomas, the response in our patient suggests that this is possible.
For the use of ipilimumab for the treatment of metastatic mucosal melanoma there are case studies mostly on pretreated patients. In a series of 30 patients (76% of which with the dosing of 3 mg/kg bodyweight, 24% with 10 mg per/kg) 1 patient responded with a complete remission, 1 patient with a PR, and 5 patients with an SD. In a series of 71 patients in the Italian “early access program” a response rate of 12.5% and a 36% rate of SD was observed.
On the use of PD-1 inhibitors in mucosal melanomas there are individual case reports.[37–39] A pooled analysis of mucosal melanomas in a variety of trials using nivolumab (n = 86), nivolumab plus ipilimumab (n = 35), or ipilimumab (n = 36) provided evidence for an effect of nivolumab in mucosal melanomas. The median progression-free survival and response rates were 2.96 months and 23.2% for nivolumab, 5.85 months and 37.2% for nivolumab plus ipilimumab, and 2.69 months and 8.3% for ipilimumab, respectively. This corresponds well with our data showing a long-lasting response in 2/7 patients treated with PD-1 inhibitors.
In our study, mucosal melanomas displayed a poor prognosis with metastasis often being already present at the time of initial diagnosis.
We could confirm the recommendation for an adjuvant radiation of the primary tumor region on patients with head/neck mucosal melanomas in order to significantly lower the risk of local recurrence.
In case of metastazation considered inoperable targeted therapies and immunotherapies with checkpoint inhibitors can be considered. PD-1 inhibitors or their combination with ipilimumab appear to show the highest response rates and longest progression-free survival. In case of a KIT mutation, additional analysis of NRAS is recommended before treating with a KIT-inhibitor. In the rare event of a BRAF V600 mutation, targeted therapy analogous to cutaneous melanomas is recommended.
The limitations of this study are the small number of patients and the long period of patient acquisition, in particular the low number of patients with targeted and immunotherapy treatment. Therefore, no conclusions with regard to therapy standards can be achieved.
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Keywords:Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.
CTLA-4; immunotherapy; mucosal melanoma; PD-1 inhibitor; prognosis; radiotherapy; targeted therapy