Mucosal melanoma (MM) is an aggressive and clinically complex malignancy made more challenging by its relative rarity. Of the 68,130 cases of melanoma diagnosed in 2010 in the United States, only 0.8% to 1.8% of these arise from mucosal surfaces.1–3 Despite a common cell of origin, MM is a clinical and pathologic entity distinct from its more common cutaneous counterpart. MM can arise from any mucosal surface of the body, with 55% arising from the head and neck, 24% from the anorectal mucosa, and 18% from the vulvovaginal mucosa.2 Disease arising from the mucosa of the pharynx, larynx, urinary tract, cervix, esophagus, gallbladder, or other mucosal sites is less common.
This article summarizes the clinical, pathologic, and molecular features, and the diagnostic and therapeutic considerations for the management of MM, underscoring the similarities and differences from cutaneous melanoma (CM). Furthermore, the distinct clinical features and management implications unique to melanoma arising from the mucosal surfaces of the head and neck, the anorectal region, and the female genital tract are highlighted.
Epidemiology and Clinical Features of Mucosal Melanoma
The epidemiology and clinical features of MM differ significantly from those of CM (Table 1). MM develops at a later age than does CM, with a median age at diagnosis of 70 years compared with 55 years for CM.2 Although CM is slightly more common in men, with a male-to-female ratio of 1.2:1.0, MM is more commonly diagnosed in women, primarily because of the occurrence of melanoma arising within the female genital tract, with a male-to-female ratio of 1.0:1.8.2 The incidence of CM has been increasing at rate greater than that of any other cancer in the United States, whereas the incidence of MM has remained stable over time.4 Although CM is associated with exposure to ultraviolet light, the anatomic location of MM precludes this exposure as a predisposing risk factor, and no clear predisposing risk factors have been identified in MM.
Clinical and Pathologic Features of Cutaneous and Mucosal Melanomas
CM is uncommon in blacks, Asians, and Hispanics, with an annual age-adjusted incidence of only 1% of that observed in whites. Although the absolute incidence of MM is greatest in whites, the proportion of MM in blacks, Asians, and Hispanics is greater than that observed in whites. Overall, MM does not seem to have a racial predilection, except possibly melanoma arising from the oral cavity, which may be more common in black and Japanese populations.2
When diagnosed early, most CMs are cured with surgical excision; however, patients with locoregionally advanced or metastatic disease fare poorly, with a median overall survival of 6 to 8 months. Outcomes for MM are inferior irrespective of stage at diagnosis. Although the 5-year overall survival rate for CM is 80%,5 the rate for MM is only 25% (Figure 1A).2 Prognosis depends on the primary site of disease (Figure 1B).2 Patients with disease arising from the head and neck, anorectal mucosa, and vulvovaginal mucosa have 5-year overall survival rates of 31.7%, 19.8%, and 11.4%, respectively, with survival rates for MM of the head and neck (MMHN) significantly better than those for MM from the other subsites.2 Locoregional nodal metastasis at presentation is more frequent in MM than in CM. Although 9% of CMs will present with locoregional nodal disease, 21% of MMHNs, 61% of anorectal mucosal melanomas (ARMMs), and 23% of vulvovaginal mucosal melanomas (VVMMs) present with involved nodes.2 Patients with nodal disease have poorer outcomes, with a 5-year survival rate of 16.4% versus 38.7% for those with negative nodes.2 The inferior outcomes observed in MM may be partly due to later diagnosis because of lack of clinical suspicion in the setting of relative rarity, more advanced disease at initial diagnosis, and the rich lymphovascular supply of the mucosal surfaces.
Mucosal Melanoma of the Head and Neck
MMHN accounts for 6.3% to 8% of all melanomas arising in this region, occurring, in decreasing order of frequency, within the nasal cavity, oral cavity, nasal sinuses, pharynx, larynx and upper esophagus.2,3,6 Of MMHNs, 70% to 80% arise in the paranasal sinuses and nasal cavity, representing 4% of all sinonasal tumors.2 Although the exact site of origin of these tumors is often difficult to determine because of the presence of locally advanced disease, 80% of sinonasal melanomas and approximately 55% of all MMHNs arise from the nasal cavity, with the remainder arising from the paranasal sinuses.6 Within the nasal cavity, the turbinates and nasal wall are most commonly involved, followed by the nasal septum. Among the paranasal sinuses, the maxillary sinuses are most commonly involved, followed by the ethmoid, frontal, and sphenoid sinuses. Oral cavity MM constitutes 0.5% of all oral malignancies and approximately 40% of all MMHNs, and most commonly affects the hard palate and upper alveolus.2,6
Median age at diagnosis ranges from 60 to 69 years7; however, oral cavity MM presents at a younger age compared with sinonasal melanomas, with many affected individuals younger than 40 years.8 The frequency of disease in men and women is equivalent in most7,9 but not all reports.8,10 As with other sinonasal malignancies, inhaled and ingested carcinogens, such as tobacco and formaldehyde, are implicated as potential risk factors for the development of sinonasal MM, although strong evidence is lacking.3 Oral melanosis has been implicated as a possible precursor lesion for up to one-third of oral melanoma cases.8
(A) Disease-specific survivals for patients diagnosed with all stages of cutaneous melanoma, stage III or IV cutaneous melanoma, and mucosal melanoma. (B) Disease-specific survivals for patients diagnosed with mucosal melanoma arising from the head and neck, anorectal region, and vulvovaginal region. Data from Chang AE, Karnell LH, Menck HR. The National Cancer Data Base report on cutaneous and noncutaneous melanoma: a summary of 84,836 cases from the past decade. The American College of Surgeons Commission on Cancer and the American Cancer Society. Cancer 1998;83:1664–1678.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 10, 3; 10.6004/jnccn.2012.0034
The clinical course differs significantly for MM of the oral cavity and sinonasal MM. MM of the oral cavity more frequently presents with regional nodal involvement, with 25% of cases presenting with nodal metastases compared with 6% of sinonasal melanomas.6,7 Although distant metastases are uncommon at presentation, occurring in 4% to 10% of cases,6,11 most patients ultimately develop distant disease. The 5-year overall survival rate for MMHN ranges from 17% to 35%6,9,12; however, prognosis varies by primary disease site, with 5-year overall survival rates of 15% to 30%, 12%, and 0% to 5% for MM arising from the nasal cavity, oral cavity, and paranasal sinuses, respectively. Features such as early stage, pigmented lesion, female sex, and young age may be associated with better outcomes.11 Other studies, however, have found no associations among age, sex, site of primary, histologic appearance, or presence of nodal disease and prognosis.6
Anorectal Mucosal Melanoma
ARMM represents 0.4% to 1.6% of all melanomas and 1% of all malignancies arising in the anorectal region. One-third of ARMMs are located within the anal canal, with 42% arising from the rectum and 25% with an indeterminate site of origin.13 Unlike MM arising from other sites, the incidence of ARMM is increasing.13 ARMM occurs at a median age of 60 to 70 years, with a male-to-female ratio of 0.75.3,13,14 This finding is confounded by the fact the women are more likely to undergo perineal evaluation as part of routine examinations. HIV infection may be a risk factor. Prognosis is poor, with a 5-year overall survival rate of 10% to 20% and median survival of 25 months.15 Up to 60% of cases will present with locoregional nodal involvement, with 20% of cases having distant disease at presentation.2,14,16 Perineural invasion is a poor prognostic marker in ARMM.17 Other prognostic factors may include stage at diagnosis, lymph node involvement, and tumor thickness.15,16
Vulvovaginal Mucosal Melanoma
Melanomas arising from the female urogenital tract account for up to 7% of melanomas in women.18 They most commonly arise from the vulva, with fewer than 5% arising from the vagina. In 20% of cases, the precise site of origin cannot be identified. Vulvar melanoma is the second most common malignant disease of the vulva, and accounts for 5% to 10% of all vulvar malignant disease, with an annual incidence of less than 0.2 per 100,000 women per year.19,20 Eighty-five percent arise from the labia minora, clitoris, or the inner, glabrous, nonhairy portion of the labia majora, with the remaining 15% arising from the outer, nonglabrous, hair-bearing portion of the labia majora.18 Vaginal melanoma accounts for fewer than 3% of all vaginal tumors and constitutes approximately 1% of all melanomas in women, with an estimated incidence of 0.026 per 100,000 women per year.21,22 Vaginal melanomas more commonly arise in the lower third of the vagina on the anterior wall.21 Vaginal melanoma occurs most commonly in the sixth to seventh decades of life,21 with vulvar melanoma most commonly affecting postmenopausal women between 60 and 70 years of age.20 Chronic inflammatory disease, viral infections, and chemical irritants are implicated risk factors of VVMM.
The clinical course differs significantly between vulvar and vaginal melanoma. Although outcomes are poor for both diseases, patients with vaginal melanoma have inferior 5-year overall survival rates, ranging from 5% to 25%, compared with those with vulvar melanomas, whose rates are 8% to 55%.4,18,22 For vaginal melanoma, tumor size (< 3 vs. ≥ 3 cm) has been shown to predict survival in some series. Nodal involvement in vulvar melanoma is of prognostic significance, with 5-years survival rates of 15% for those with nodal metastasis and 54% for those without.18,19 Ulceration, tumor thickness, and presence of mitotic activity of the primary lesion may also be prognostic in this disease.18,19 Additional poor prognostic factors implicated in vulvar melanoma include advanced age, high mitotic rate, amelanosis, emergence from a preexisting nevus, tumor extension to the lateral labia majora, central anatomic location, angioinvasion, DNA nondiploidy, low income, and nonwhite race.18,19
Recommendations for Staging Systems by Primary Site of Disease
Staging of Mucosal Melanoma
The 7th edition of the AJCC staging system for melanoma is used for CM, with tumor thickness, mitotic rate, presence of ulceration, and regional nodal status the dominant prognostic features.5 However, because the histology and implicated prognostic features of MM differ from those of CM, the AJCC staging system for CM cannot be universally applied to MM.
No proposed staging system has been shown to reliably divide cases of MM into low- or high-risk cohorts, regardless of site of origin. In the absence of a universal MM prognostic staging system, the Ballantyne staging system can be used.23 Although initially devised for MMHN, this system can be applied to all MM subsites (Table 2). Because most patients present with localized stage I disease and because of the lack of clear association between nodal involvement and prognosis in all MM subtypes, the prognostic utility of this system is limited; however, because of its ease of use and broad applicability, it remains a commonly accepted staging system for MM.
Because of the unique constellation of prognostic features implicated for MM arising from distinct anatomic regions, several additional site-specific MM staging systems have been devised. For MMHN, proposed staging systems have included the Prasad microstaging system, which is applicable for stage I (node-negative) MMHN24; the Thompson staging system for sinonasal and nasopharyngeal MM25; and the AJCC T-staging system for MM of the nasal cavity and paranasal sinuses (Appendix 1).26 In 2010, the AJCC developed a specific staging system for MMHN that has been shown to be predictive of outcome.27 This system was developed with 2 key factors in mind: 1) the overwhelmingly poor prognosis of MMHN, and 2) the notion that MMHN prognosis is dependent on the local, regional, and distant burden of disease. To reflect the poor prognosis even in low-volume disease, the most limited form of disease is considered stage III disease. Staging ranges from III to IVA, IVB, and IVC (as defined in Appendix 1), depending on local extent and presence of regional and distant disease. Therefore, any evidence of primary MMHN is at least stage III disease. MM that does not invade bone, deep soft tissue, cartilage, or skin is T3. All other lesions are T4a unless they invade brain, dura, skull base, lower cranial nerves (IX, X, XI, XII), masticator space, carotid artery, prevertebral space, or mediastinal structures. Stage IV is divided into 3 categories, as in other head and neck subsites, to reflect advanced but not unresectable local disease with or without regional disease (IVA), highly advanced local disease (IVB), and distant disease (IVC).
Although no specific staging system has been developed for ARMM, some series have shown the Ballantyne staging system to have prognostic significance.14 Proposed staging systems for VVMM include Breslow depth,28 Clark level,29 Chung level,30 the International Federation of Gynecology and Obstetrics (FIGO) staging systems for vulvar and vaginal carcinoma,31 and the AJCC staging system for CM (Appendix 2).5 Although none of these staging systems are useful predictors of prognosis in vaginal melanoma, the 2002 modified AJCC staging system for CM was shown to be predictive of recurrence-free survival for vulvar melanoma.32,33
Based on currently available data, it is recommended that the AJCC staging systems for MMHN and CM be used for MMHN and vulvar melanoma, respectively (Table 2). Further work is required to develop useful staging systems for melanomas arising from the anorectal and vaginal regions.
Locoregional Management of Mucosal Melanoma
Surgical Management of the Primary Site and Regional Lymph Nodes
As in CM, surgery is the most important therapeutic modality for MM, with complete resection providing the greatest chance for cure. Because of the lentiginous growth pattern frequently associated with MM, the multifocal nature of this disease, and anatomic constraints, however, wide negative margins can be difficult to achieve. Despite aggressive surgical resection, local recurrence rates are as high as 50% to 90%.10
Sinonasal MM may require craniofacial resection when disease extends into the cribriform plate, orbital exenteration for gross orbital involvement, and radical nasal exenteration for diffuse mucosal disease. Evidence suggests that complete endoscopic resections may be accomplished with less morbidity and equivalent local control.34 Thus, advances to enable less-destructive and less-deforming endoscopy resections may allow for satisfactory local control without sacrificing prognosis. This is of particular relevance in the setting of multifocal recurrences after definitive therapy. Oral cavity MM is approached surgically in the same manner as squamous cell carcinoma. Local resection should be accompanied by appropriate reconstruction using free flaps for mandibular, soft tissue, or structural deficits.
Historically, surgical management of MM involved radical procedures, including abdominoperineal resection (APR) for ARMM and pelvic exenteration for VVMM; procedures accompanied by significant morbidity and functional limitations.15 Although some series suggest improved local control with these more aggressive surgical procedures, available retrospective data suggest no difference in overall survival with more conservative wide local excision.14–19,33,35 Because local recurrence occurs concomitantly with distant metastasis in most cases, improved local control has limited benefit for survival. Because most patients ultimately develop distant disease regardless of the primary surgical procedure, patient preference and quality of life considerations are critical in determining the extent of surgery. Conservative surgery in the form of wide local excision has generally replaced APR for ARMM and pelvic exenteration for VVMM.
Although regional lymph node status is a critical prognostic factor for intermediate-depth CM, the implications of nodal involvement in MM are less clear and no widely accepted standard of care exists for the management of regional lymph nodes in this disease. Sentinel lymph node evaluation has become a routine procedure in CM, and seems feasible in MM.36,37 Because of the uncertainty surrounding the prognostic significance of nodal involvement in MMHN and ARMM, however, the role of sentinel node evaluation in these diseases is undefined. Furthermore, even if the sentinel node is positive, the effects of subsequent completion node dissection on overall survival are partly unknown, given the frequent development of metastases independent of nodal status.17,20,32 Nevertheless, in the absence of systemic disease, therapeutic neck dissection followed by radiation therapy in MMHN is likely to improve regional control.26,38 The postoperative morbidity of neck dissection is considerably less compared with that after inguinal or pelvic node dissection, and aggressive management of the lymph node basins should be performed only after the risks and benefits are considered.
Role of Radiation Therapy in Mucosal Melanoma
Radiosensitivity studies of melanoma cells in vitro and in vivo suggest a significant ability of melanoma to repair sublethal damage. Variation, however, exists in radioresistance, as shown in CM and MM cell lines, and recent studies suggest that melanoma is as radiosensitive as other solid tumors.39 Although surgical resection is recommended as the primary therapeutic modality for localized disease, definitive radiotherapy can achieve local control in up to 85% of cases.7,40 Because of the high rate of local recurrence after surgery, particularly in MMHN, postoperative radiotherapy has become widely used, with some series showing an improvement in locoregional control.26,41,42 Most studies failed to identify an impact on overall survival with adjuvant radiotherapy, although these analyses are complicated by a selection bias for the use of radiotherapy in more advanced cases.
Optimal dosing, fractionation schedules, and clear indications for radiotherapy have yet to be defined. Use of a dose per fraction higher than 4 to 6 Gy may be required to improve radiation responsiveness.43 Some retrospective studies noted better local control with modification of dose schedule, whereas others note both improved local control and overall survival.41 An update of the MD Anderson experience suggests that standard fractionation greater than 54 Gy results in superior results compared with hypofractionated schedules.26 The Radiation Therapy Oncology Group assessed 2 fraction size schemas and randomized 137 patients with advanced disease to 8 Gy per fraction in 4 fractions or 2.5 Gy per fraction in 20 fractions. Although no significant difference was observed, the small number of patients and the advanced stage of disease permitted may have obscured any true difference.44 Caution should be taken if considering hypofractionation for MM in areas containing neural tissues, where dose per fraction is critical. Ongoing studies are evaluating newer technologies that yield increased precision in delivery of radiotherapy, such as using protons and heavy ions that take advantage of higher linear energy transfer.
Systemic Therapy for Advanced Mucosal Melanoma
No systemic therapy has been shown to improve outcomes specifically in patients with advanced MM, and treatment of these patients has generally paralleled the management of advanced cutaneous disease. Until 2011, the FDA-approved agents available for the treatment of advanced melanoma were limited to dacarbazine and high-dose interleukin (IL)-2, with limited clinical benefit associated with either drug. Approval for each was based on trials that included primarily patients with CM. Although data regarding the efficacy of these treatments in MM are limited, some retrospective series of various systemic regimens suggested that these agents produced responses in MM equivalent to those observed in CM.
More recently, 2 additional agents were approved for melanoma, with each having the advantage of a demonstrable survival advantage over dacarbazine and IL-2. Ipilimumab, a fully human IgG1 antibody targeting cytotoxic T lymphocyte–associated antigen 4, was approved in March 2011 based on a phase III clinical trial showing an overall survival benefit of 3.6 months in previously treated patients with advanced CM compared with a glycoprotein 100.45 A subsequent trial showed improved survival with ipilimumab and dacarbazine versus dacarbazine alone in previously untreated patients with advanced CM.46 Although no study of ipilimumab has been conducted specifically in patients with advanced MM, anecdotal cases of benefit have been observed.
Vemurafenib, a small molecule inhibitor with specificity for BRAF harboring a substitution of glutamic acid for valine at position 600 (V600E), was approved in August 2011 based on the BRIM3 trial that randomized patients with advanced CM harboring the BRAF V600E mutation to treatment with vemurafenib or dacarbazine.47 Vemurafenib achieved a response rate of 48%, a 63% decrease in hazard of death, and a 74% decrease in hazard of tumor progression. Importantly, vemurafenib is only effective in tumors driven by an activating BRAF mutation. Although BRAF mutations are present in 45% to 50% of CM, the prevalence is less than 10% in MM.48,49 The question of whether vemurafenib in MM harboring BRAF mutations will have similar efficacy to that observed in CM harboring these mutations has not been rigorously investigated; however, administration of vemurafenib in this setting is a reasonable consideration.
MMs harbor recurrent mutations and/or amplifications of the receptor tyrosine kinase KIT, which are alterations infrequently observed in CM.48 A trial conducted by Memorial Sloan-Kettering Cancer Center screened 295 tumor samples for the presence of KIT mutations and amplification, and observed these alterations in 25% of MM.49 Of the 25 evaluable patients treated with imatinib, an inhibitor of multiple tyrosine kinases, including KIT, 13 had MM, 3 of whom experienced a major response. Full results from a study by Guo et al.50 and interim results of a study by Fisher et al.51 also show the efficacy of imatinib in select patients with melanoma harboring KIT alterations. Responses in the phase II trials were highly variable, but patterns have emerged suggesting that tumors with specific KIT alterations, particularly in exons 11 and 13, are more likely to benefit from KIT inhibition than are those with amplification alone or with KIT alterations affecting other regions. This suggests that not all KIT alterations are equally predictive of benefit to therapeutic inhibition.
Ongoing assessment of specific KIT mutations as predictive biomarkers for targeted therapy is critical, and improvement in the ability to identify true driving mutations in KIT may result in better patient selection. Results from ongoing work in the identification of primary and secondary resistance to KIT inhibition, other systemic therapies, and predictive biomarkers of response may allow optimization of patient selection for specific treatments and the development of effective combination therapies.
Conclusions
The increasing understanding of the unique biology of MM arising from distinct anatomic regions and resultant ongoing refinements in staging and locoregional management over the past several decades has led to important improvements in how this disease is managed. Advances in immunotherapy and the recently identified molecular subsets of MM characterized by driving alterations in BRAF or KIT have led to unprecedented clinical outcomes in patients with advanced disease. Further refinements of systemic therapy for MM and the potential application of this therapy in the adjuvant setting hold the promise of improving outcomes in this challenging disease.
Staging Systems for Mucosal Melanoma of the Head and Neck
Staging Systems for Vulvovaginal Melanoma
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