International Journal of
Radiation Oncology biology
physics
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Clinical Investigation
Mucosal Melanoma of the Head and Neck: A Systematic Review of the Literature Stanislav Lazarev, BA,* Vishal Gupta, MD,y Kenneth Hu, MD,z Louis B. Harrison, MD,z and Richard Bakst, MDy *University of Vermont, College of Medicine, Burlington, Vermont; yDepartment of Radiation Oncology, Mount Sinai Medical Center, New York, New York; and zBeth Israel Medical Center, St. Luke’s-Roosevelt Hospital Center, New York, and Ear Infirmary, New York, New York Received Dec 2, 2013, and in revised form Mar 14, 2014. Accepted for publication Mar 25, 2014.
Primary mucosal melanoma of the head and neck (MMHN) comprises approximately 1% of all malignant melanomas. It presents more commonly in an elderly population and has no significant gender predominance. Given its rarity, most evidence of the causes, behavior, and treatment approaches for MMHN originates from isolated case reports and retrospective series. Between 1945 and 2011, at least 1951 cases of MMHN have been reported in the literature. Despite numerous technological developments in surgery and radiation therapy, as well as advances in systemic modalities, MMHN is an aggressive malignancy with a very poor prognosis. Complete surgical excision with clear margins remains the primary treatment modality. Adjuvant postoperative radiation therapy may improve locoregional control but does not appear to affect survival. Definitive particle radiation therapy promises to provide high rates of local control for nonoperable patients. Recent molecular evidence suggests that proto-oncogene KIT aberrations in a subset of mucosal melanomas may represent a potential diagnostic value and serve as a therapeutic target for tyrosine kinase inhibitors in an adjuvant setting for patients with advanced MMHN. Ó 2014 Elsevier Inc.
Introduction Mucosal melanoma of the head and neck (MMHN) is a rare oncological entity comprising approximately 10% of melanomas arising in the head and neck and approximately 1% of all malignant melanomas (1-3). It is more common in an elderly population and has a poor prognosis given its high rates of local relapse and distant metastases. The overall 5-year survival rate for localized MMHN is 24% (4), whereas the corresponding rate for localized cutaneous melanoma is in the range of 79% to 97% (5). Because of its rarity, most of
Reprint requests to: Richard Bakst, MD, Radiation Oncology Associates, 1184 Fifth Ave, 1st Floor, Box 1236, New York, NY 10029. Tel: (212) 241-3545; E-mail:
[email protected] Int J Radiation Oncol Biol Phys, Vol. 90, No. 5, pp. 1108e1118, 2014 0360-3016/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2014.03.042
the existing literature describing treatment approaches for MMHN includes isolated case reports and retrospective series with relatively small sample sizes. Nonetheless, wide surgical excision is generally considered a primary treatment modality for localized MMHN whenever the lesion is resectable. The role of radiation therapy (RT) has not yet been well established, but RT is often used in the postoperative adjuvant setting to improve locoregional control (6). The use of systemic therapies has so far demonstrated little to no survival benefit (7,8). Despite numerous institutional experiences, there is no clear consensus on the optimal
Conflict of interest: none.
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RT technique in the management of MMHN. Given the rarity of the disease, a randomized controlled trial is not feasible. Therefore, we performed a systematic review of the current literature and provide a comprehensive summary of findings as they pertain to the available therapies for MMHN.
Methods and Materials A literature search for studies published up to August 13, 2013, was conducted using PubMed database. The search identified 82 articles using search items “sinonasal mucosal melanoma” and 286 articles using search items “mucosal melanoma head neck.” All titles and abstracts of the studies retrieved in the original search were further screened to identify those addressing the use of RT in patients with MMHN. Included studies were retrospective series that reported outcomes of treatment with RT. Excluded were studies discussing mucosal melanoma of sites other than the head and neck, review papers, case reports, meta-analysis, and studies written in a language other than English. The following information was extracted from the identified series, where available: total number of patients, patient’s sex, age, race, primary tumor sites, and RT technique including type of radiation, total dose and fractionation regimen, and setting of RT (definitive vs adjuvant). Major outcomes in regards to survival, control, and recurrence were identified in each study.
Results Epidemiology Most patients with MMHN present at an older age, typically in their seventh decade (6-17). The age of presentation of MMHN is comparable to that of cutaneous melanoma. According to the recent Surveillance Epidemiology and End Results cancer statistics review, from 2006 to 2010, the median age at diagnosis for cutaneous melanoma was 61 years of age (18). Distribution of the disease between men and women appears to be equal, although in several series, men were affected markedly more than women (6, 9, 19-21), whereas in other studies the disease was more common in women (10-16, 22). Similarly to cutaneous melanoma (23), incidence of MMHN appears to be highest in whites (2, 4, 8, 12, 24-27). However, considering that 5 of the identified series took place in countries with predominantly Asian populations (9, 10, 13, 28, 29), MMHN may have a distinct predisposition for those racial groups and geographic areas. In fact, recent evidence suggests that mucosal melanoma is the second most common subtype of malignant melanomas in Asian populations (30).
Molecular and immunohistochemical profiling Genetic aberrations implicated in the pathogenesis of MMHN have not yet been clearly described. Some of the
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currently available molecular and immunohistochemical data with respect to mucosal melanomas have been extrapolated from the literature on cutaneous subtypes. Most recent data on immunohistochemical and genetic profiling of different subtypes of melanoma, including MMHN and mucosal melanomas of other sites, point to the potential significance of the KIT gene alterations (31-37) and a lesser role for the BRAF gene mutations in melanomas of mucosal origin (35, 38-41). Activating mutations in the BRAF gene, whose incidence has been demonstrated to be increased in malignant cutaneous melanomas, appear to be rare in mucosal melanomas (42). Antonescu et al (42) suggested that mutations in BRAF may be dependent on exposure to solar ultraviolet radiation. Therefore, it may be appropriate to assume that the anatomic location makes the presence of this genetic abnormality less likely in MMHN. In a large retrospective study of 1112 cases of melanoma at the MD Anderson Cancer Center (38), all mucosal melanomas were determined to be BRAF wild type, whereas BRAF mutations were identified only in cutaneous melanomas. These findings argue against the potential clinical utility of BRAF as a diagnostic marker or therapeutic target in MMHN. In contrast, somatic mutations in the KIT gene, which were identified in a small number of cutaneous melanomas (43), appear to have an increased incidence in mucosal melanomas. In a study of 102 cases of primary melanomas of skin and mucosa, Curtin et al (31) demonstrated that 39% of mucosal melanomas carried mutations and/or an increased copy number of KIT. That study also observed an increased expression of KIT protein in acral and mucosal melanomas, further supporting its role in tumorigenesis of specific subtypes of melanoma. Given evidence of a likely pathogenetic role of the KIT gene in a number of mucosal melanomas (31, 33-35, 37), including those of the head and neck, screening for KIT aberrations may have a potential diagnostic value, and the gene may present a future therapeutic target.
Prognostic factors Younger age at diagnosis appears to be a significant prognostic factor in MMHN (3, 4, 10, 12, 13, 16, 22). In the 2 largest retrospective series to date with a total of 563 patients (3, 4), younger patients had better survival rates than those presenting at a more advanced age, but no differences in prognosis between men and women were noted. Most of the series found no significant association between sex and survival (3, 4, 9-14, 16, 20, 24, 44-46). Most of the series assessing the primary tumor site as a prognostic factor were unable to find a statistically significant association between this variable and improved survival or control (2, 3, 7, 8, 12, 24, 44, 45). In the second largest retrospective review of 259 patients with MMHN (3), the anatomic location of primary disease was not predictive of survival. Contrary to these findings, at least 3 series (6, 9, 21) noted that patients with primary mucosal melanoma lesions
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originating in the nasal cavity had improved survival, whereas in 2 other studies (11, 16), patients with oral cavity mucosal melanomas had a significantly improved 5-year overall survival rate. It should be noted that in 1 of those studies (11), patients with oral lesions were more likely to undergo radical surgery and, hence, had a better chance for survival. Achievement of clear margins was related to better clinical outcome in several studies (6, 13, 47). Notably, negative margins were a significant prognostic factor for survival in a large Korean study of 115 cases of mucosal melanoma (13), 49 of which had MMHN. Pigmented lesions in MMHN may also be associated with favorable outcomes (3, 22, 28). A potential delay in detecting and subsequently diagnosing amelanotic mucosal melanomas may explain their overall worse prognosis. On the other hand, hyperpigmentation in melanotic lesions has been proposed to represent a radial growth phase of the mucosal tumor preceding the submucosal invasion by years and, hence, offers better prognosis (45).
sinonasal mucosal melanoma (4), the 5-year overall survival rate was found to be 24%. Poor survival in patients with MMHN has been attributed to the aggressive local and hematogenous spread of disease (7). Regardless of the treatment approach, local control in MMHN remains less than optimal (Table 1). In the second largest retrospective study, the authors reported a local failure rate of 52% among 259 patients with MMHN who either underwent wide local excision or received combined treatment therapies (3). This finding confirms aggressive behavior of MMHN and the tendency to recur locally after initial treatment. It has been proposed that high local recurrence rates may be a result of the multifocal nature of primary disease or clinically unapparent lymphatic spread of mucosal melanoma cells (9). Therefore, radical wide local excision should be considered in the early clinical stage of the disease. There is evidence suggesting that locoregional failure could be a significant prognostic factor in patients with MMHN (15, 25, 28, 46, 47). Benlyazid et al (15) observed that patients with primary MMHN with locoregional recurrence after initial treatment failure had an increased risk of distant recurrence compared to those without locoregional recurrence. Similarly, a multi-institutional study of 94 patients with MMHN in northern Japan (28) reported that the 4-year overall survival rate in the patients who had not developed regional failure was significantly higher than the corresponding rate in those patients who had (42% vs 23%, respectively, P