Your activity: 5258 p.v.
< Back
your limit has been reached. plz Donate us to allow your ip full access, Email: [email protected]

Mucosal melanoma

Mucosal melanoma
Authors:
Richard D Carvajal, MD
Omid Hamid, MD
Charlotte Ariyan, MD, PhD
Section Editors:
Michael B Atkins, MD
Russell S Berman, MD
Deputy Editor:
Sonali Shah, MD
Literature review current through: Feb 2022. | This topic last updated: Dec 22, 2020.

INTRODUCTION — Melanomas may arise from the mucosal epithelium lining the respiratory, alimentary, and genitourinary tracts, all of which contain melanocytes, as well as from the skin.

Mucosal melanomas generally carry a worse prognosis than those arising from cutaneous sites. Because of the rarity of mucosal melanoma, and because of the unique biology and clinical challenges of mucosal melanoma arising from each anatomic location, our understanding of these malignancies and their optimal management remains limited.

General aspects of mucosal melanoma, as well as the specific approach to patients with mucosal melanomas arising in the head and neck, vulvovaginal, and anorectal regions, are discussed here.

MUCOSAL VERSUS CUTANEOUS MELANOMA — There are substantial differences in mucosal as opposed to cutaneous melanomas that have important implications for patient management.

Epidemiology — Mucosal melanomas are rare and account for approximately 1 percent of all melanomas [1]. Mucosal melanomas arise primarily in the head and neck, anorectal, and vulvovaginal regions (55, 24, and 18 percent of cases, respectively). Rarer sites of origin include the urinary tract, gall bladder, and small intestine.

In general, patients diagnosed with mucosal melanomas are older, with a median age of 70 years, although mucosal melanoma of the oral cavity frequently presents at a younger age [2,3]. Mucosal melanoma is more common in females than males, primarily due to the development of disease in the genital tract [1,4,5].

Although the incidence of cutaneous melanoma has been increasing rapidly in the United States, the incidence of mucosal melanoma has generally remained stable over time [6,7]. Cutaneous melanoma is associated with exposure to ultraviolet light, but the anatomic location of mucosal melanoma precludes ultraviolet exposure as a risk factor. No clear predisposing risk factors have been identified in this disease. (See "Risk factors for the development of melanoma".)

Mucosal melanomas make up a greater proportion of all melanomas diagnosed in blacks, Asians, and Hispanics when compared with melanomas occurring in whites, reflecting the much lower incidence of cutaneous melanoma in these populations [8]. While less than 2 percent of melanomas occurring in white non-Hispanic patients arise in mucosal sites, 9 percent of melanomas diagnosed in black or Hispanic patients have a mucosal origin [1]. Despite a greater proportion of mucosal melanomas in blacks, Asians, and Hispanics, the absolute incidence of mucosal melanoma remains greater in whites.

Biology and management — An estimated 20 percent of mucosal melanomas are multifocal [9], compared with less than 5 percent of those arising in the skin [10]. Approximately 40 percent of mucosal melanomas are amelanotic, compared with less than 10 percent of cutaneous melanomas [10].

Staging of mucosal melanomas varies depending upon the primary site. However, a simplified staging system, which was originally developed for melanomas of the head and neck, can be applied to all cases of mucosal melanoma [11]. This staging system classifies tumors into three stages:

●Stage I – clinically localized disease

●Stage II – regional nodal involvement

●Stage III – distant metastatic involvement

Regardless of the primary site, wide local excision of mucosal melanoma offers the best chance for prolonged disease-free survival when technically feasible. However, complete resection with negative margins is frequently difficult because of the lentiginous growth pattern frequently associated with mucosal melanoma, the multifocality of disease, and anatomic constraints.

Most patients will ultimately develop distant metastatic disease regardless of the completeness of surgical resection. While the five-year overall survival rate for cutaneous melanoma is 80 percent, the rate for mucosal melanoma is only 25 percent [1]. In addition to having an inferior outcome from the time of diagnosis, patients with mucosal melanoma may have a poorer stage-matched survival than other melanoma subtypes from the time of development of clinical metastatic disease [12]. The significant disease complications that result from primary site failure must be balanced against the morbidity of a more aggressive resection. Thus patient preferences, as well as quality of life considerations, are critical in determining the extent of surgery.

MUCOSAL MELANOMA OF THE HEAD AND NECK

Clinical presentation — Mucosal melanomas account for less than 10 percent of all melanomas arising in the head and neck region, while more than 90 percent arise in the skin. Mucosal melanomas of the head and neck commonly occur in the following locations [13-18]:

●Nasal cavity (most commonly involving the turbinates and nasal wall) – 55 percent

●Paranasal sinuses (most commonly involving the maxillary and ethmoid sinuses) – 15 percent

●Oral cavity (most commonly involving the hard palate and upper alveolus) – 25 percent

Much less commonly, mucosal melanomas arise in the pharynx [19], larynx [20], or esophagus [21,22].

Patients with sinonasal mucosal melanomas frequently present with nasal obstruction, epistaxis, or loss of smell [23-25]. Mucosal melanoma of the oral cavity typically presents as a painless bleeding mass, as an area of ulceration, as a region of mucosal discoloration, or with ill-fitting dentures [15].

Approximately 60 percent of mucosal melanomas arising from the oral cavity are identified incidentally during routine dental examination. Irregular isolated areas of pigmentation within the oral mucosa must be differentiated from melanosis, a benign condition which is common in blacks and generally is symmetrical. Such lesions should be biopsied.

Evaluation and staging — Work-up for patients with mucosal melanoma arising from the head and neck should include clinical examination with endoscopic inspection for paranasal disease, computed tomography (CT) and/or magnetic resonance imaging (MRI) of the primary site of disease, and CT and/or positron emission tomography (PET) imaging to assess for lymph node involvement or distant metastases. Regional lymph node involvement has been estimated to be present at presentation in approximately 25 percent of those with oral cavity lesions and 6 percent of those with sinonasal mucosal melanoma [1].

The American Joint Committee on Cancer (AJCC) staging system for mucosal melanoma arising from the head and neck is now generally used for this subset of disease and reflects the overwhelmingly poor prognosis of this disease (table 1) [26]. The AJCC head and neck stage system differs from that for cutaneous melanoma, in which prognosis depends upon the local, regional, and distant burden of disease. Staging begins at stage III as the most limited form of disease, to reflect the poor prognosis in these patients, and includes three subcategories of stage IV disease (IVA, IVB, and IVC), depending upon the local extent and presence of regional and distant disease [27-29].

Management

Surgery — Complete surgical excision is the primary treatment for AJCC stage III and IVA mucosal melanomas of the head and neck if the lesion can be resected with negative margins. Surgery is not recommended as primary therapy for patients with lymph node involvement (IVB) or distant metastases (IVC), unless there is a need for local control of disease. Adjuvant radiation therapy (RT) should be considered if complete resection is possible. (See 'Radiation therapy' below.)

Mucosal melanomas of the oral cavity are approached surgically in the same manner as squamous cell carcinomas at the same site. Local resection should be accompanied by appropriate reconstruction using free flaps for mandibular, soft tissue, or structural defects. Similarly, mucosal melanoma of the larynx and pharynx should be managed by the appropriate surgical approach to achieve local control.

Craniofacial resection has been used when tumor invades the skull base, either as part of the initial presentation or as an isolated local recurrence [30,31]. Endoscopic resections are being performed more commonly and may be accomplished with less morbidity and equivalent local control [32].

Despite aggressive surgical management, local recurrence is very common [2,15,18,24]. Factors associated with local recurrence include tumor size, incomplete resection, and vascular invasion [15,33]. The median time to first recurrence in the head and neck is 6 to 12 months [13,24].

Although the initial site of relapse is frequently local or regional, such recurrence usually is a harbinger of disseminated disease, with most patients dying of distant rather than uncontrolled local disease [2,13,23,34,35]. Additional surgery can be considered for locally recurrent disease; however, the decision to proceed with re-resection for local or regional recurrence should be considered on a case-by-case basis.

●The incidence of nodal disease in sinonasal mucosal melanoma is less than 10 percent; thus, elective lymph node dissection is not routinely recommended in these cases [15].

●Melanoma arising from the oral cavity is associated with nodal disease in up to 25 percent of cases [15,18], and some investigators recommend elective lymph node dissection in this subgroup of patients [36]. As in squamous cell carcinoma of the head and neck, the regional lymph nodes can be addressed at the same time as the primary resection, clearing the first and second echelons of nodes. When reconstruction using free flaps is required, the neck must be entered and clearance of the nodal disease can be considered.

●Therapeutic neck dissection in the setting of clinically evident disease can be accomplished with limited morbidity and may be performed for optimal regional control. However, no significant difference in five-year overall survival has been observed in patients with and without lymph node recurrence, suggesting that the treatment of the nodes should be based on need for local control and symptomatic treatment [13].

Sentinel lymph node biopsy does not have an established role in patients with mucosal melanoma of the head and neck, although identification of sentinel lymph nodes in patients with mucosal melanoma appears to be feasible [37,38].

Radiation therapy — RT may have a role, either as an adjuvant following surgery in carefully selected patients [29], or when surgery is not appropriate or feasible:

●Local recurrence occurs in 29 to 79 percent of cases despite aggressive surgery and can be clinically devastating [2,18,34,39-41]. Observational data and one meta-analysis have reported an improvement in locoregional control with adjuvant RT, although there is no proven impact on survival [25,34,41-45]. Such benefit, however, has not been observed in all series and the role of RT has not been definitively established in clinical trials [15,46]. Some centers recommend routine postoperative RT for those with palpable lymph nodes or the finding of extracapsular extension following wide local excision and neck dissection. RT is not used if lesions are close to the eye or central nervous system.

●Primary RT should be considered for patients who are not candidates for resection or when an adequate resection margin is not possible [34]. Tumor control rates ranging from 61 to 85 percent have been reported with definitive RT in patients with mucosal melanomas arising from the head and neck [47,48]. Analysis of these series is complicated by the selection bias toward the use of RT in patients with more extensive tumors and narrow or involved surgical margins.

Optimal dosing and fractionation schedules have not been established for RT either as primary therapy or as an adjuvant to surgery. (See "Radiation therapy in the management of melanoma".)

Metastatic disease — Treatment of metastatic mucosal melanoma of the head and neck is largely based upon experience in patients with cutaneous melanoma. (See 'Systemic therapy' below.)

Prognosis — The prognosis in patients with mucosal melanoma arising in the head and neck is generally poor, with reported five-year survival rates of 12 to 30 percent for primary lesions of the nasal cavity, oral cavity, and paranasal sinuses [15,29,49-51].

VULVOVAGINAL MELANOMA — Melanomas arising from the female urogenital tract occur primarily in the vulva and vagina (95 and 3 percent, respectively) [1]; melanomas arising elsewhere in the urinary bladder, urethra, or cervix are rarer [52-56].

Although vulvar melanomas account for less than 1 percent of all melanomas, they represent 10 percent of all malignant tumors involving the vulva [57,58]. A subset of vulvar melanomas, particularly those arising from the outer, non-glabrous hair-bearing portion of the labia majora, may share common risk factors with cutaneous melanoma. Some vulvar melanomas may develop from contiguous nevi [59]. Chronic inflammatory disease, viral infections, chemical irritants, and genetic factors have also been implicated as risk factors [60]. (See "Vulvar cancer: Epidemiology, diagnosis, histopathology, and treatment".)

Evaluation and staging — Patients with vulvovaginal melanoma commonly present with pruritus, vaginal bleeding, a vaginal discharge, dyspareunia, or a mass [61-66]. Work-up for patients with vulvovaginal melanoma should include clinical assessment with pelvic examination, computed tomography (CT) and/or magnetic resonance imaging (MRI) of the primary site of disease, and CT and/or positron emission tomography (PET) imaging to assess for the presence of distant disease [67].

Vulvar melanoma staging — Vulvar melanomas should be staged according to the tumor, node, metastasis (TNM) system for cutaneous melanoma [67]. (See "Tumor, node, metastasis (TNM) staging system and other prognostic factors in cutaneous melanoma", section on 'Eighth edition AJCC TNM staging'.)

The Gynecologic Oncology Group performed a prospective clinical-pathologic study of primary vulvar melanomas evaluating the predictive value of the microscopic staging systems described by Clark [68], Breslow [69], and Chung [70], as well as the International Federation of Gynecology and Obstetrics (FIGO) system and the 1992 American Joint Committee on Cancer (AJCC) melanoma staging system. In this study, the AJCC cutaneous melanoma staging system was found to be the most significant predictor of recurrence-free survival in women with this disease [71]. Subsequent studies have provided additional evidence that using the modified AJCC staging system for cutaneous melanoma has prognostic utility for vulvar melanoma [72,73].

The overall prognosis is a function of stage of disease at presentation. Outcomes are illustrated by the five-year relative survival rates in 223 women diagnosed between 1985 and 1989 in the United States based upon data in the National Cancer Database [57]:

●Stage 0 – 77 percent

●Stage I – 70 percent

●Stage II – 50 percent

●Stage III – 48 percent

●Stage IV – 24 percent

Vaginal melanoma staging — No staging system has been demonstrated to be a useful predictor of prognosis in vaginal melanoma, although tumor size (<3 cm versus ≥3 cm), has been shown to predict survival in some series [74,75]. In the absence of such a prognostic staging system for this disease, the previously described simplified clinical staging system can be used for the purposes of standardization [11]. In this system, stages I, II, and III correspond to clinically localized disease, regional lymph node involvement, and distant metastases, respectively.

Because the majority of patients with mucosal melanoma present with localized stage I disease, the prognostic utility of this system is limited; however, due to its ease of use and broad applicability, it remains a reasonable staging system for patients with vaginal melanoma in the absence of a predictive alternative.

Locoregional management — Most patients with vulvovaginal melanoma ultimately develop distant metastatic disease regardless of the primary surgical procedure; thus, patient preference and quality-of-life considerations are critical factors in determining the extent of surgery for the initial management.

Vulvar melanoma — Wide local excision has generally replaced pelvic exenteration for vulvovaginal melanoma for women without evidence of distant metastases. Surgical management of vulvar melanomas should include resection of the primary tumor by wide local excision. Radical vulvectomy is reserved for large tumors primarily to obtain local disease control. Melanomas <1 mm thick should be treated with 1 cm skin margins; if anatomically feasible, margins can be extended to 2 cm for thicker melanomas [76,77]. The excision contains all layers of skin and subcutaneous tissues, extending to the muscular fascia below.

More radical procedures are associated with significant morbidity. Although some series suggested improved local control with more aggressive surgical procedures, the impact of improved local control upon survival is limited by the concomitant development of distant metastases in the majority of cases. Available retrospective data suggest no difference in overall survival with more conservative wide local excision [72,74,78-83].

Vaginal melanoma — Standard management of women with vaginal melanoma involves wide local excision if possible. Achieving negative margins in these cases can be difficult without pelvic exenteration given the high frequency of multifocality and anatomic constraints. However, the impact of such radical surgery upon survival when compared with more conservative procedures (with or without radiation therapy [RT]) is unclear. Thus, surgery may be combined with RT in select cases. (See 'Radiation therapy' above.) [84].

Regional lymph nodes — Evaluation of sentinel nodes is feasible in women with vulvovaginal melanoma, but the role of this approach is uncertain [60,85,86]. While small series suggest a survival benefit for elective regional lymphadenectomy in patients with vulvar melanoma, a more contemporary study performed by the Gynecologic Oncology Group identified positive nodes as merely a prognostic factor along with tumor thickness. In this series, only 7 out of 56 patients undergoing a lymphadenectomy had positive nodes [71]. In addition, several studies have demonstrated that radical vulvectomy with bilateral inguinofemoral lymphadenectomy does not confer a survival benefit when compared with wide local excision alone for vulvar melanoma [83,87].

Metastatic disease — Treatment of metastatic vulvovaginal mucosal melanoma is largely based upon experience in patients with cutaneous melanoma. (See 'Systemic therapy' below.)

Prognosis — Despite aggressive therapy, the prognosis remains poor for most patients with mucosal melanoma arising in the vulva or vagina. While patients with vulvar melanoma have five-year survival rates of 24 to 77 percent, those with vaginal melanoma have five-year survival rates of 5 to 25 percent [63,76,88-92].

ANORECTAL MELANOMA

Clinical presentation — Anorectal mucosal melanoma accounts for approximately 0.05 percent of all colorectal malignancies and 1 percent of all anal canal cancers [93]. The site of origin is the rectum or anal canal in 42 and 33 percent of cases, respectively, while the primary site cannot be determined in the remainder. Although the risk factors for anorectal mucosal melanoma are not known, epidemiologic data suggest that there is an increased risk associated with human immunodeficiency virus infection [93-95]. (See "HIV infection and malignancy: Management considerations", section on 'Melanoma'.)

The majority of cases arise from the mucocutaneous junction; however, they can also arise from the skin of the anal verge, the transitional epithelium of the anal canal, or the rectal mucosa (figure 1). Identification of the primary site of disease is critical to separate anal cutaneous from anal mucosal melanomas. While primary site of disease in vulvovaginal melanoma has prognostic relevance, this is not the case for anorectal melanoma [96].

Patients typically present with bleeding, a mass, anorectal pain, or a change in bowel habits. Occasionally, melanoma is an incidental finding on pathologic evaluation of a hemorrhoidectomy or anal polyp specimen. Anorectal melanoma is pigmented in only one-third of cases. Most patients present with lesions that are >2 mm thick. Regional lymph node involvement is found in approximately 60 percent of patients at presentation [1], and distant metastases are present at diagnosis in approximately 30 percent of cases [97-102].

Staging evaluation — The initial evaluation of patients with anorectal melanoma should include a rectal examination, rectal ultrasound, and CT and/or PET imaging to assess for distant metastases.

Anorectal melanoma is excluded from the American Joint Committee on Cancer (AJCC) staging system for anal cancers. Retrospective series have used a simple system in which localized disease only, regional lymph node involvement, and distant metastases are classified as stages I, II, and III, respectively [103].

Patients with lymph node metastases or distant metastases at presentation have an especially poor prognosis. A review of 183 patients with anorectal mucosal melanoma identified in the Surveillance, Epidemiology, and End Results (SEER) database found the following [97]:

●Stage I – median survival, 24 months; 5-year survival, 26.7 percent

●Stage II – median survival, 17 months; 5-year survival, 9.8 percent

●Stage III – median survival, 8 months; 5-year survival, 0 percent

Factors that may adversely affect prognosis in patients with localized disease include the presence of perineural invasion, tumor size and thickness, and the presence of amelanotic melanoma [98,99,104-106].

Management

Surgery — The primary goal of surgery is to perform a negative margin, sphincter-sparing excision. Abdominoperineal resection is reserved for patients with bulky local disease and for carefully selected patients with local recurrence [107]. Inguinal lymphadenectomy is reserved for patients with clinically apparent disease, given the morbidity of bilateral inguinal node dissection and lack of proven benefit from an elective dissection.

Multiple retrospective series have looked at the impact of the extent of surgery on long-term outcomes. Some series suggested improved local control with abdominoperineal resection, a procedure accompanied by a high morbidity rate and functional limitations [102,104,108]; however, retrospective data suggest that there is no difference in overall survival (OS) with more conservative wide local excision [97,98,105,109,110].

The benefit of improved local control upon survival is limited. Most patients ultimately develop distant disease regardless of the primary surgical procedure; thus patient preference and quality-of-life considerations are critical in determining the extent of surgery.

The most important factor in surgery appears to be the ability to achieve negative (R0) surgical resection margins [105,109]. In a series of 251 cases from the Swedish National Cancer Registry, the five-year survival rates following surgical excision for those in whom an R0 resection was achieved was 19 percent, compared with 6 percent in those in whom a complete local excision was not possible [109]. On multivariate analysis, resection status and tumor stage were significantly associated with prognosis, but the type of resection (abdominoperineal resection or local excision) was not significant.

Mesorectal, pelvic sidewall, and inguinal lymph nodes are at risk for involvement in anorectal mucosal melanoma. However, available data suggest that lymph node metastasis does not predict outcome in patients undergoing radical resection, and sentinel lymph node biopsy does not have an established role in these patients [105,111,112].

Adjuvant radiation therapy — Adjuvant radiation therapy for anorectal melanoma may improve locoregional control despite a lack of demonstrable impact upon OS [113]. Sphincter-sparing local excision followed by hypofractionated RT has been used as an alternative to abdominoperineal resection in an effort to prevent local recurrence and preserve quality of life. In a series of 54 patients from MD Anderson Cancer Center treated over a 20-year period, this approach achieved local control in 82 percent of cases; however, the five-year OS rate was only 30 percent [114].

Metastatic disease — Treatment of metastatic anorectal melanoma is largely based upon experience in patients with cutaneous melanoma. (See 'Systemic therapy' below.)

Prognosis — The reported five-year survival rates for patients with anorectal melanoma are approximately 20 percent [104,105,109,115].

SYSTEMIC THERAPY

Adjuvant therapy — Adjuvant immunotherapy with checkpoint inhibitors is a treatment option for patients with cutaneous melanoma and resected positive regional lymph nodes. There are only limited data on adjuvant systemic therapy in patients with mucosal melanoma. (See "Adjuvant and neoadjuvant therapy for cutaneous melanoma".)

The only data on the efficacy of systemic therapy for mucosal melanoma in the adjuvant setting come from a phase II randomized trial of interferon versus chemotherapy in Chinese patients with resected mucosal melanoma [116]. In this trial, 189 patients who had undergone complete resection of a mucosal melanoma were randomly assigned to observation, postoperative interferon alfa-2b (15 MU/m2/day for five days/week x four weeks followed by 9 MU/m2 three times per week for 48 weeks) or chemotherapy (temozolomide 200 mg/m2 days 1 to 5 plus cisplatin 25 mg/m2 days 1 to 3, every three weeks for six cycles).

With a median follow-up of 27 months, the median relapse-free survival was significantly prolonged with chemotherapy (20.8 versus 9.4 and 5.4 months, respectively, compared with interferon and observation). Estimated overall survival (OS) was also significantly increased (49 versus 40 and 21 months, respectively).

These results require replication in a broader patient population before adjuvant chemotherapy can be considered a standard of care for Western patients with mucosal melanoma. This approach might be considered in carefully selected patients who have undergone a potentially curative resection, have no serious coexisting illness, and have the potential for long-term survival excluding their risk of melanoma related mortality.

Adjuvant immunotherapy with nivolumab has an established role in cutaneous melanoma and lymph node involvement. This approach can be considered for patients with mucosal melanoma [29], preferably in the context of a formal clinical trial. (See "Adjuvant and neoadjuvant therapy for cutaneous melanoma".)

Metastatic disease — Data on the systemic treatment of patients with metastatic melanoma arising from a mucosal site are very limited, and treatments have been patterned after those used for metastatic melanoma from a cutaneous primary.

A retrospective, single-institution study reported on 74 patients evaluable for response to first-line and 43 evaluable for response to second-line systemic therapy. Cytotoxic therapy represented 82 and 51 percent of first-line and second-line regimens, respectively. The best response achieved in the first-line setting was similar for single-agent (10 percent; 95% CI 1 to 32 percent) and combination alkylator therapy (8 percent; 95% CI 2 to 21 percent). Median OS from first-line treatment was 10.3 months (95% CI 8.7 to 13.9 months) [117].

Mutation status of tumor — All patients with mucosal melanoma should have their tumors assayed for the presence or absence of a driver mutation at the V600 site in BRAF. Patients with a tumor that does not contain a BRAF mutation should have their tumor assessed for the presence of a driver mutation in KIT.

Targeted therapy — An understanding of the molecular pathogenesis of mucosal melanoma has provided important insights that are leading to the development of targeted therapies for specific subsets of patients with metastatic disease. Approximately 10 percent of mucosal melanomas harbor activating mutations in BRAF and another 25 percent have somatic mutations or amplification of KIT [118,119]. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations".)

Three clinical trials of imatinib mesylate, a small molecule inhibitor of KIT and other tyrosine kinases, demonstrated this agent to be ineffective in a molecularly unselected patient population with advanced melanoma [120-122]. However, several case reports have demonstrated rapid and durable tumor responses to KIT inhibition in patients with melanoma harboring KIT mutations [123,124].

Three subsequent phase II trials of imatinib have been conducted; unlike the prior trials, each of these studies required the presence of melanoma harboring somatic alteration of KIT for eligibility.

●In one study, 6 of 25 evaluable patients had a radiographic response [118]. Two patients had durable complete responses, two patients had durable partial responses, and two patients had transient partial responses. All six patients who responded had either an L576P (exon 11) or a K642E (exon 13) KIT mutation. Both patients who had a complete response had exon 11 L576P mutations with concurrent amplification.

●In another series, 43 patients with a KIT alteration were treated with imatinib [125]. A partial response was observed in 10 cases (23 percent); overall, 18 patients had evidence of tumor regression. One patient with a KIT amplification without a mutation responded. Of the patients with KIT mutations, only patients with mutations in exons 11 and 13 responded.

●In a third study, 24 evaluable patients with either a mutation or amplification in KIT were treated with imatinib; 17 patients had mucosal melanoma, six had acral melanoma, and one had melanoma arising in chronically sun damaged skin [126]. KIT mutations were identified in 13 patients. Overall, partial responses were observed in 7 of 13 patients (54 percent) with a KIT mutation; no partial responses were seen in patients with KIT amplification without a KIT mutation.

A similar level of activity has been seen with nilotinib in patients with KIT-mutant melanoma [127-129]. In the largest of these phase II studies, 42 patients with KIT-mutated advanced melanoma were treated with nilotinib [129]. Overall, 11 patients had a partial response (26 percent), and 20 patients (48 percent) had stable disease.

Patients with KIT-mutant melanoma have also been reported to respond to other targeted inhibitors of KIT, such as sorafenib [130], dasatinib [131], and sunitinib [132]. Notably, all of these patients had KIT mutations involving exon 11 or 13.

For patients without a V600 BRAF mutation but with a KIT mutation, use of a KIT inhibitor (eg, imatinib) may provide an important treatment option, particularly in patients who have symptomatic disease and/or are not candidates for immunotherapy, preferably in the context of a formal clinical trial. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'KIT mutations (acral and mucosal melanoma)'.)

A trial of a BRAF inhibitor (vemurafenib, dabrafenib) in combination with a MEK inhibitor (cobimetinib, trametinib) should be considered in patients with advanced mucosal melanoma harboring a BRAF mutation. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'KIT mutations (acral and mucosal melanoma)'.)

Checkpoint inhibitor immunotherapy

Anti-CTLA4 immunotherapy — The anti-CTLA4 monoclonal antibody ipilimumab has been shown to significantly prolong survival in some patients with cutaneous melanoma. There are no randomized trials with ipilimumab in mucosal melanoma. (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation".)

In a multicenter, retrospective analysis of 33 patients with unresectable or metastatic mucosal melanoma treated with ipilimumab, one immune-related complete response, one immune-related partial response, six immune-related stable disease, and 22 immune-related progressive disease cases were observed [133]. By the modified World Health Organization (WHO) criteria, there was one immune-related complete response, one immune-related partial response, five immune-related stable disease, and 23 immune-related progressive disease at approximately 12 weeks after initiation of therapy. The median OS from the time of the first dose of ipilimumab was 6.4 months (range: 1.8 to 26.7 months). Evidence of antitumor activity has also been observed in an expanded access program in patients with mucosal melanoma [134].

Additional investigation is necessary to clarify the role of ipilimumab in patients with mucosal melanoma.

Anti-PD-1 immunotherapy — The anti-programmed cell death protein 1 (PD-1) monoclonal antibodies nivolumab and pembrolizumab significantly prolong survival in patients with cutaneous melanoma. Although there are no randomized clinical trials specifically addressing the activity of these agents in patients with mucosal or acral melanomas, these have shown efficacy in this subset in post-hoc analyses of trials enrolling a more general population [135-138]. Compiled data from clinical trials focused on all subsets of patients with metastatic melanoma suggest that those with mucosal melanoma respond less well to single-agent immunotherapy than patients with cutaneous melanoma and therefore may derive particular benefit from the added tumor response typically seen with combination treatments. However, although there is clear data that combination therapies result in improved response rates, comparative OS data between single-agent and combination strategies in patients with mucosal melanoma are lacking.

In an exploratory post-hoc analysis of three randomized trials enrolling almost 1600 patients with stage III or IV melanoma, 84 patients had mucosal melanoma, of whom 33 had received prior ipilimumab [137]. Among patients with mucosal melanoma, treatment with pembrolizumab (at several doses) resulted in an overall objective response rate of 19 percent, and median progression-free survival (PFS) and OS of 2.8 and 11.3 months, respectively. Median duration of response was 27.6 months, suggesting durable antitumor activity.

Combination anti-PD-1 and anti-CTLA4 therapy has shown benefits over single-agent anti-PD-1 therapy in clinical trials. A combined analysis of six studies using nivolumab identified 86 patients with advanced mucosal melanoma treated with nivolumab alone and 35 treated with the combination of nivolumab plus ipilimumab [136]. The analysis included results from 665 patients with cutaneous melanoma treated with nivolumab alone and 326 treated with nivolumab plus ipilimumab.

●The objective response rate for patients with mucosal melanoma treated with nivolumab alone was 23 percent compared with 41 percent for those with cutaneous melanoma; median PFS was 3.0 versus 6.2 months.

●The objective response rate for patients with mucosal melanoma treated with nivolumab plus ipilimumab was 37 versus 60 percent for those with cutaneous melanoma. The median PFS was 5.9 versus 11.7 months.

A retrospective series analyzed outcomes in 35 patients with metastatic mucosal melanoma and 25 with metastatic acral melanoma who were treated with pembrolizumab or nivolumab; 77 percent of patients had received prior ipilimumab [135]. The objective response rate in those with mucosal melanoma was 23 percent, and for those with acral melanoma, the response rate was 32 percent; the median PFS for both groups was four months.

Additional prospective investigation is necessary to clarify the role of anti-PD-1 immunotherapy alone and in combination with ipilimumab in patients with mucosal melanoma.

Biochemotherapy — Retrospective series suggest that response rates for patients with metastatic mucosal melanoma to cisplatin-based biochemotherapy regimens are similar to those in patients with cutaneous disease. (See "Cytotoxic chemotherapy for metastatic melanoma".)

●In 18 patients with metastatic anorectal mucosal melanoma, cisplatin-based chemotherapy was combined with interferon alfa-2b and/or interleukin (IL)-2 [139]. Eight patients (44 percent) achieved major responses, including two (11 percent) complete responses. With a median follow-up time of 12.2 months (range, 3.5 to 43.7 months), the median time to progression of the 15 patients available for follow-up was six months and the median OS was 12 months.

●In another series, 11 patients with metastatic vulvovaginal mucosal melanoma were treated with cisplatin-based chemotherapy plus interferon alfa-2b and/or IL-2 [140]. Four patients (36 percent) achieved a partial response. With a median follow-up of 10 months, the median time to progression was three months and the median OS was 10 months.

●In a third series, 15 patients with metastatic mucosal melanoma of the head and neck were treated with cisplatin-based biochemotherapy regimens [141]. After a median follow-up of 13 months, three patients (20 percent) achieved a partial response, and four patients (27 percent) had complete response. The median time to disease progression for all 15 patients was 10 months, and the median OS was 22 months.

EXPERIMENTAL APPROACHES

●Imiquimod – Complete resection of mucosal melanoma is challenging due to the frequent multifocal presentation as well as anatomic considerations. While radiotherapy can lead to effective local control of unresectable disease, such therapy is limited by tissue tolerance and toxicity. Thus, alternative local therapies are needed.

The topical immune modifier imiquimod has been used experimentally to treat lentigo maligna and cutaneous metastases from invasive melanoma. In three patients with recurrent mucosal melanoma, topical treatment with imiquimod resulted in local control of disease [142]. However, regional and/or distant metastases developed in all three cases (see "Lentigo maligna: Clinical manifestations, diagnosis, and management", section on 'Topical imiquimod') [143-147]. This approach remains experimental and should not be used outside a protocol setting.

●Toripalimab plus axitinib – In preliminary results from a phase Ib trial, the combination of toripalimab (a PD-1 inhibitor) with axitinib (a vascular endothelial growth factor receptor [VEGFR] inhibitor) demonstrated clinical activity in patients with metastatic mucosal melanoma, with an objective response rate of 49 percent [148]. Although toripalimab has regulatory approval in China for patients with metastatic melanoma, the combination of toripalimab and axitinib in patients with metastatic mucosal melanoma remains investigational. The use of other checkpoint inhibitor immunotherapy agents in those with metastatic disease is discussed separately. (See 'Checkpoint inhibitor immunotherapy' above.)

SURVEILLANCE AFTER SURGERY — There are no studies detailing the optimal approach to surveillance following treatment of mucosal melanoma. The approach has been based upon extrapolation from patients with cutaneous melanoma. (See "Staging work-up and surveillance of cutaneous melanoma", section on 'Surveillance'.)

A retrospective, single-institution study evaluating the pattern of initial metastases in 81 patients identified the most common initial sites of metastasis as the lungs, liver, and nonregional lymph nodes, regardless of the primary site of disease. The rate of brain involvement as an initial site of metastasis was 7 percent, and no primary site was free of risk. Given these data, surveillance imaging strategies for mucosal melanoma could include chest, abdomen and pelvis, and brain imaging [117].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Melanoma screening, prevention, diagnosis, and management".)

SUMMARY AND RECOMMENDATIONS

●Melanomas may arise from the mucosal epithelium lining the respiratory, alimentary, and genitourinary tracts, all of which contain melanocytes, as well as from the skin. The most common sites of involvement are the head and neck, vulvovaginal, and anorectal regions. Mucosal melanomas generally carry a worse prognosis than those arising from cutaneous sites, with most patients developing recurrent and disseminated disease.

●Mucosal melanomas are rare. Treatment recommendations for patients with mucosal melanoma are based almost exclusively upon small, retrospective studies that include heterogeneous patient populations treated at single institutions over a long time period.

●The standard initial management for locoregionally confined mucosal melanoma is complete wide local surgical resection, which offers the best chance for long-term survival. Most patients will ultimately develop distant metastatic disease regardless of the achievement of local control with initial treatment. Thus, patient preferences as well as quality-of-life considerations are critical in determining the extent of surgery for resection of the primary lesion.

•Mucosal melanomas of the head and neck mucosal are approached surgically in the same manner as squamous cell carcinomas at the same site. (See 'Management' above.)

•More conservative wide local excision has generally replaced pelvic exenteration for vulvovaginal melanoma and abdominoperineal resection for anorectal melanoma. (See 'Locoregional management' above and 'Management' above.)

•In carefully selected patients, radiation therapy (RT) may be an alternative to control local disease when a complete resection is not feasible. Adjuvant RT may also decrease the incidence of local recurrences in carefully selected patients, although no impact on survival has been demonstrated. (See 'Radiation therapy' above and 'Locoregional management' above and 'Adjuvant radiation therapy' above.)

●The approach to management of systemic metastases from a mucosal melanoma is based upon the treatment of metastatic cutaneous disease. Advances in immunotherapy and targeted therapy for metastatic melanoma may offer important treatment options as more data become available, and further evaluation of therapies such as anti-programmed cell death protein 1 (PD-1)-based treatments are warranted in this disease. (See 'Metastatic disease' above.)

REFERENCES

  1. 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.
  2. Meleti M, Leemans CR, de Bree R, et al. Head and neck mucosal melanoma: experience with 42 patients, with emphasis on the role of postoperative radiotherapy. Head Neck 2008; 30:1543.
  3. Rapini RP, Golitz LE, Greer RO Jr, et al. Primary malignant melanoma of the oral cavity. A review of 177 cases. Cancer 1985; 55:1543.
  4. Sutherland CM, Chmiel JS, Henson DE, Winchester DP. Patient characteristics, methods of diagnosis, and treatment of mucous membrane melanoma in the United States of America. J Am Coll Surg 1994; 179:561.
  5. Pandey M, Mathew A, Abraham EK, et al. Primary malignant melanoma of the mucous membranes. Eur J Surg Oncol 1998; 24:303.
  6. Patrick RJ, Fenske NA, Messina JL. Primary mucosal melanoma. J Am Acad Dermatol 2007; 56:828.
  7. McLaughlin CC, Wu XC, Jemal A, et al. Incidence of noncutaneous melanomas in the U.S. Cancer 2005; 103:1000.
  8. Cress RD, Holly EA. Incidence of cutaneous melanoma among non-Hispanic whites, Hispanics, Asians, and blacks: an analysis of california cancer registry data, 1988-93. Cancer Causes Control 1997; 8:246.
  9. Lotem M, Anteby S, Peretz T, et al. Mucosal melanoma of the female genital tract is a multifocal disorder. Gynecol Oncol 2003; 88:45.
  10. Carvajal RD, Spencer SA, Lydiatt W. Mucosal melanoma: a clinically and biologically unique disease entity. J Natl Compr Canc Netw 2012; 10:345.
  11. Ballantyne AJ. Malignant melanoma of the skin of the head and neck. An analysis of 405 cases. Am J Surg 1970; 120:425.
  12. Kuk D, Shoushtari AN, Barker CA, et al. Prognosis of Mucosal, Uveal, Acral, Nonacral Cutaneous, and Unknown Primary Melanoma From the Time of First Metastasis. Oncologist 2016; 21:848.
  13. Manolidis S, Donald PJ. Malignant mucosal melanoma of the head and neck: review of the literature and report of 14 patients. Cancer 1997; 80:1373.
  14. Nandapalan V, Roland NJ, Helliwell TR, et al. Mucosal melanoma of the head and neck. Clin Otolaryngol Allied Sci 1998; 23:107.
  15. Patel SG, Prasad ML, Escrig M, et al. Primary mucosal malignant melanoma of the head and neck. Head Neck 2002; 24:247.
  16. McLean N, Tighiouart M, Muller S. Primary mucosal melanoma of the head and neck. Comparison of clinical presentation and histopathologic features of oral and sinonasal melanoma. Oral Oncol 2008; 44:1039.
  17. DeMatos P, Tyler DS, Seigler HF. Malignant melanoma of the mucous membranes: a review of 119 cases. Ann Surg Oncol 1998; 5:733.
  18. Bachar G, Loh KS, O'Sullivan B, et al. Mucosal melanomas of the head and neck: experience of the Princess Margaret Hospital. Head Neck 2008; 30:1325.
  19. Johnson IJ, Warfield AT, Smallman LA, Watkinson JC. Primary malignant melanoma of the pharynx. J Laryngol Otol 1994; 108:275.
  20. Amin HH, Petruzzelli GJ, Husain AN, Nickoloff BJ. Primary malignant melanoma of the larynx. Arch Pathol Lab Med 2001; 125:271.
  21. Archer HA, Owen WJ. Primary malignant melanoma of the esophagus. Dis Esophagus 2000; 13:320.
  22. Ahn JY, Hwang HS, Park YS, et al. Endoscopic and pathologic findings associated with clinical outcomes of melanoma in the upper gastrointestinal tract. Ann Surg Oncol 2014; 21:2532.
  23. Stern SJ, Guillamondegui OM. Mucosal melanoma of the head and neck. Head Neck 1991; 13:22.
  24. Lee SP, Shimizu KT, Tran LM, et al. Mucosal melanoma of the head and neck: the impact of local control on survival. Laryngoscope 1994; 104:121.
  25. Moreno MA, Roberts DB, Kupferman ME, et al. Mucosal melanoma of the nose and paranasal sinuses, a contemporary experience from the M. D. Anderson Cancer Center. Cancer 2010; 116:2215.
  26. Lydiatt WM, Brandwein-Gensler M, Kraus DH, et al. Mucosal melanoma of the head and neck. In: AJCC Cancer Staging Manual, 8th ed, Amin MB (Ed), Springer, New York 2017. p.163.
  27. Prasad ML, Patel SG, Huvos AG, et al. Primary mucosal melanoma of the head and neck: a proposal for microstaging localized, Stage I (lymph node-negative) tumors. Cancer 2004; 100:1657.
  28. Thompson LD, Wieneke JA, Miettinen M. Sinonasal tract and nasopharyngeal melanomas: a clinicopathologic study of 115 cases with a proposed staging system. Am J Surg Pathol 2003; 27:594.
  29. Nenclares P, Ap Dafydd D, Bagwan I, et al. Head and neck mucosal melanoma: The United Kingdom national guidelines. Eur J Cancer 2020; 138:11.
  30. Ganly I, Patel SG, Singh B, et al. Craniofacial resection for malignant melanoma of the skull base: report of an international collaborative study. Arch Otolaryngol Head Neck Surg 2006; 132:73.
  31. Lund VJ, Howard DJ, Harding L, Wei WI. Management options and survival in malignant melanoma of the sinonasal mucosa. Laryngoscope 1999; 109:208.
  32. Hanna E, DeMonte F, Ibrahim S, et al. Endoscopic resection of sinonasal cancers with and without craniotomy: oncologic results. Arch Otolaryngol Head Neck Surg 2009; 135:1219.
  33. Panje WR, Moran WJ. Melanoma of the upper aerodigestive tract: a review of 21 cases. Head Neck Surg 1986; 8:309.
  34. Krengli M, Masini L, Kaanders JH, et al. Radiotherapy in the treatment of mucosal melanoma of the upper aerodigestive tract: analysis of 74 cases. A Rare Cancer Network study. Int J Radiat Oncol Biol Phys 2006; 65:751.
  35. Loree TR, Mullins AP, Spellman J, et al. Head and neck mucosal melanoma: a 32-year review. Ear Nose Throat J 1999; 78:372.
  36. Medina JE, Ferlito A, Pellitteri PK, et al. Current management of mucosal melanoma of the head and neck. J Surg Oncol 2003; 83:116.
  37. Stárek I, Koranda P, Benes P. Sentinel lymph node biopsy: A new perspective in head and neck mucosal melanoma? Melanoma Res 2006; 16:423.
  38. Baptista P, Garcia Velloso MJ, Salvinelli F, Casale M. Radioguided surgical strategy in mucosal melanoma of the nasal cavity. Clin Nucl Med 2008; 33:14.
  39. Owens JM, Roberts DB, Myers JN. The role of postoperative adjuvant radiation therapy in the treatment of mucosal melanomas of the head and neck region. Arch Otolaryngol Head Neck Surg 2003; 129:864.
  40. Nakashima JP, Viégas CM, Fassizoli AL, et al. Postoperative adjuvant radiation therapy in the treatment of primary head and neck mucosal melanomas. ORL J Otorhinolaryngol Relat Spec 2008; 70:344.
  41. Temam S, Mamelle G, Marandas P, et al. Postoperative radiotherapy for primary mucosal melanoma of the head and neck. Cancer 2005; 103:313.
  42. Benlyazid A, Thariat J, Temam S, et al. Postoperative radiotherapy in head and neck mucosal melanoma: a GETTEC study. Arch Otolaryngol Head Neck Surg 2010; 136:1219.
  43. Yii NW, Eisen T, Nicolson M, et al. Mucosal malignant melanoma of the head and neck: the Marsden experience over half a century. Clin Oncol (R Coll Radiol) 2003; 15:199.
  44. Caspers CJI, Dronkers EAC, Monserez D, et al. Adjuvant radiotherapy in sinonasal mucosal melanoma: A retrospective analysis. Clin Otolaryngol 2018; 43:617.
  45. Grant-Freemantle MC, Lane O'Neill B, Clover AJP. The effectiveness of radiotherapy in the treatment of head and neck mucosal melanoma: Systematic review and meta-analysis. Head Neck 2021; 43:323.
  46. Wu AJ, Gomez J, Zhung JE, et al. Radiotherapy after surgical resection for head and neck mucosal melanoma. Am J Clin Oncol 2010; 33:281.
  47. Wada H, Nemoto K, Ogawa Y, et al. A multi-institutional retrospective analysis of external radiotherapy for mucosal melanoma of the head and neck in Northern Japan. Int J Radiat Oncol Biol Phys 2004; 59:495.
  48. Koto M, Demizu Y, Saitoh JI, et al. Multicenter Study of Carbon-Ion Radiation Therapy for Mucosal Melanoma of the Head and Neck: Subanalysis of the Japan Carbon-Ion Radiation Oncology Study Group (J-CROS) Study (1402 HN). Int J Radiat Oncol Biol Phys 2017; 97:1054.
  49. Cheng YF, Lai CC, Ho CY, et al. Toward a better understanding of sinonasal mucosal melanoma: clinical review of 23 cases. J Chin Med Assoc 2007; 70:24.
  50. Dauer EH, Lewis JE, Rohlinger AL, et al. Sinonasal melanoma: a clinicopathologic review of 61 cases. Otolaryngol Head Neck Surg 2008; 138:347.
  51. Samstein RM, Carvajal RD, Postow MA, et al. Localized sinonasal mucosal melanoma: Outcomes and associations with stage, radiotherapy, and positron emission tomography response. Head Neck 2016; 38:1310.
  52. Katz EE, Suzue K, Wille MA, et al. Primary malignant melanoma of the urethra. Urology 2005; 65:389.
  53. Kojima T, Tanaka T, Yoshimi N, Mori H. Primary malignant melanoma of the urinary bladder. Arch Pathol Lab Med 1992; 116:1213.
  54. Khalbuss WE, Hossain M, Elhosseiny A. Primary malignant melanoma of the urinary bladder diagnosed by urine cytology: a case report. Acta Cytol 2001; 45:631.
  55. Clark KC, Butz WR, Hapke MR. Primary malignant melanoma of the uterine cervix: case report with world literature review. Int J Gynecol Pathol 1999; 18:265.
  56. Cantuaria G, Angioli R, Nahmias J, et al. Primary malignant melanoma of the uterine cervix: case report and review of the literature. Gynecol Oncol 1999; 75:170.
  57. Creasman WT, Phillips JL, Menck HR. A survey of hospital management practices for vulvar melanoma. J Am Coll Surg 1999; 188:670.
  58. Stang A, Streller B, Eisinger B, Jöckel KH. Population-based incidence rates of malignant melanoma of the vulva in Germany. Gynecol Oncol 2005; 96:216.
  59. Ragnarsson-Olding BK, Kanter-Lewensohn LR, Lagerlöf B, et al. Malignant melanoma of the vulva in a nationwide, 25-year study of 219 Swedish females: clinical observations and histopathologic features. Cancer 1999; 86:1273.
  60. Wechter ME, Gruber SB, Haefner HK, et al. Vulvar melanoma: a report of 20 cases and review of the literature. J Am Acad Dermatol 2004; 50:554.
  61. Piura B, Egan M, Lopes A, Monaghan JM. Malignant melanoma of the vulva: a clinicopathologic study of 18 cases. J Surg Oncol 1992; 50:234.
  62. Piura B, Rabinovich A, Dgani R. Malignant melanoma of the vulva: report of six cases and review of the literature. Eur J Gynaecol Oncol 1999; 20:182.
  63. Verschraegen CF, Benjapibal M, Supakarapongkul W, et al. Vulvar melanoma at the M. D. Anderson Cancer Center: 25 years later. Int J Gynecol Cancer 2001; 11:359.
  64. Piura B, Rabinovich A, Yanai-Inbar I. Primary malignant melanoma of the vagina: case report and review of literature. Eur J Gynaecol Oncol 2002; 23:195.
  65. Sugiyama VE, Chan JK, Shin JY, et al. Vulvar melanoma: a multivariable analysis of 644 patients. Obstet Gynecol 2007; 110:296.
  66. Borazjani G, Prem KA, Okagaki T, et al. Primary malignant melanoma of the vagina: a clinicopathological analysis of 10 cases. Gynecol Oncol 1990; 37:264.
  67. Balch CM, Buzaid AC, Soong SJ, et al. Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol 2001; 19:3635.
  68. Clark WH Jr, From L, Bernardino EA, Mihm MC. The histogenesis and biologic behavior of primary human malignant melanomas of the skin. Cancer Res 1969; 29:705.
  69. Breslow A. Thickness, cross-sectional areas and depth of invasion in the prognosis of cutaneous melanoma. Ann Surg 1970; 172:902.
  70. Chung AF, Woodruff JM, Lewis JL Jr. Malignant melanoma of the vulva: A report of 44 cases. Obstet Gynecol 1975; 45:638.
  71. Phillips GL, Bundy BN, Okagaki T, et al. Malignant melanoma of the vulva treated by radical hemivulvectomy. A prospective study of the Gynecologic Oncology Group. Cancer 1994; 73:2626.
  72. Moxley KM, Fader AN, Rose PG, et al. Malignant melanoma of the vulva: an extension of cutaneous melanoma? Gynecol Oncol 2011; 122:612.
  73. Seifried S, Haydu LE, Quinn MJ, et al. Melanoma of the vulva and vagina: principles of staging and their relevance to management based on a clinicopathologic analysis of 85 cases. Ann Surg Oncol 2015; 22:1959.
  74. Buchanan DJ, Schlaerth J, Kurosaki T. Primary vaginal melanoma: thirteen-year disease-free survival after wide local excision and review of recent literature. Am J Obstet Gynecol 1998; 178:1177.
  75. Petru E, Nagele F, Czerwenka K, et al. Primary malignant melanoma of the vagina: long-term remission following radiation therapy. Gynecol Oncol 1998; 70:23.
  76. Irvin WP Jr, Legallo RL, Stoler MH, et al. Vulvar melanoma: a retrospective analysis and literature review. Gynecol Oncol 2001; 83:457.
  77. Trimble EL. Melanomas of the vulva and vagina. Oncology (Williston Park) 1996; 10:1017.
  78. DeMatos P, Tyler D, Seigler HF. Mucosal melanoma of the female genitalia: a clinicopathologic study of forty-three cases at Duke University Medical Center. Surgery 1998; 124:38.
  79. Ragnarsson-Olding BK, Nilsson BR, Kanter-Lewensohn LR, et al. Malignant melanoma of the vulva in a nationwide, 25-year study of 219 Swedish females: predictors of survival. Cancer 1999; 86:1285.
  80. Miner TJ, Delgado R, Zeisler J, et al. Primary vaginal melanoma: a critical analysis of therapy. Ann Surg Oncol 2004; 11:34.
  81. Suwandinata FS, Bohle RM, Omwandho CA, et al. Management of vulvar melanoma and review of the literature. Eur J Gynaecol Oncol 2007; 28:220.
  82. Bradgate MG, Rollason TP, McConkey CC, Powell J. Malignant melanoma of the vulva: a clinicopathological study of 50 women. Br J Obstet Gynaecol 1990; 97:124.
  83. Trimble EL, Lewis JL Jr, Williams LL, et al. Management of vulvar melanoma. Gynecol Oncol 1992; 45:254.
  84. Irvin WP Jr, Bliss SA, Rice LW, et al. Malignant melanoma of the vagina and locoregional control: radical surgery revisited. Gynecol Oncol 1998; 71:476.
  85. de Hullu JA, Hollema H, Hoekstra HJ, et al. Vulvar melanoma: is there a role for sentinel lymph node biopsy? Cancer 2002; 94:486.
  86. Dhar KK, DAS N, Brinkman DA, et al. Utility of sentinel node biopsy in vulvar and vaginal melanoma: report of two cases and review of the literature. Int J Gynecol Cancer 2007; 17:720.
  87. Jaramillo BA, Ganjei P, Averette HE, et al. Malignant melanoma of the vulva. Obstet Gynecol 1985; 66:398.
  88. Gökaslan H, Sişmanoğlu A, Pekin T, et al. Primary malignant melanoma of the vagina: a case report and review of the current treatment options. Eur J Obstet Gynecol Reprod Biol 2005; 121:243.
  89. Bonner JA, Perez-Tamayo C, Reid GC, et al. The management of vaginal melanoma. Cancer 1988; 62:2066.
  90. Weinstock MA. Malignant melanoma of the vulva and vagina in the United States: patterns of incidence and population-based estimates of survival. Am J Obstet Gynecol 1994; 171:1225.
  91. Creasman WT, Phillips JL, Menck HR. The National Cancer Data Base report on cancer of the vagina. Cancer 1998; 83:1033.
  92. Frumovitz M, Etchepareborda M, Sun CC, et al. Primary malignant melanoma of the vagina. Obstet Gynecol 2010; 116:1358.
  93. Cagir B, Whiteford MH, Topham A, et al. Changing epidemiology of anorectal melanoma. Dis Colon Rectum 1999; 42:1203.
  94. Coté TR, Sobin LH. Primary melanomas of the esophagus and anorectum: epidemiologic comparison with melanoma of the skin. Melanoma Res 2009; 19:58.
  95. Burgi A, Brodine S, Wegner S, et al. Incidence and risk factors for the occurrence of non-AIDS-defining cancers among human immunodeficiency virus-infected individuals. Cancer 2005; 104:1505.
  96. Bello DM, Smyth E, Perez D, et al. Anal versus rectal melanoma: does site of origin predict outcome? Dis Colon Rectum 2013; 56:150.
  97. Iddings DM, Fleisig AJ, Chen SL, et al. Practice patterns and outcomes for anorectal melanoma in the USA, reviewing three decades of treatment: is more extensive surgical resection beneficial in all patients? Ann Surg Oncol 2010; 17:40.
  98. Pessaux P, Pocard M, Elias D, et al. Surgical management of primary anorectal melanoma. Br J Surg 2004; 91:1183.
  99. Cooper PH, Mills SE, Allen MS Jr. Malignant melanoma of the anus: report of 12 patients and analysis of 255 additional cases. Dis Colon Rectum 1982; 25:693.
  100. Weinstock MA. Epidemiology and prognosis of anorectal melanoma. Gastroenterology 1993; 104:174.
  101. Goldman S, Glimelius B, Påhlman L. Anorectal malignant melanoma in Sweden. Report of 49 patients. Dis Colon Rectum 1990; 33:874.
  102. Ross M, Pezzi C, Pezzi T, et al. Patterns of failure in anorectal melanoma. A guide to surgical therapy. Arch Surg 1990; 125:313.
  103. Singer M, Mutch MG. Anal melanoma. Clin Colon Rectal Surg 2006; 19:78.
  104. Brady MS, Kavolius JP, Quan SH. Anorectal melanoma. A 64-year experience at Memorial Sloan-Kettering Cancer Center. Dis Colon Rectum 1995; 38:146.
  105. Yeh JJ, Shia J, Hwu WJ, et al. The role of abdominoperineal resection as surgical therapy for anorectal melanoma. Ann Surg 2006; 244:1012.
  106. Ballo MT, Gershenwald JE, Zagars GK, et al. Sphincter-sparing local excision and adjuvant radiation for anal-rectal melanoma. J Clin Oncol 2002; 20:4555.
  107. Matsuda A, Miyashita M, Matsumoto S, et al. Abdominoperineal resection provides better local control but equivalent overall survival to local excision of anorectal malignant melanoma: a systematic review. Ann Surg 2015; 261:670.
  108. Roumen RM. Anorectal melanoma in The Netherlands: a report of 63 patients. Eur J Surg Oncol 1996; 22:598.
  109. Nilsson PJ, Ragnarsson-Olding BK. Importance of clear resection margins in anorectal malignant melanoma. Br J Surg 2010; 97:98.
  110. Droesch JT, Flum DR, Mann GN. Wide local excision or abdominoperineal resection as the initial treatment for anorectal melanoma? Am J Surg 2005; 189:446.
  111. Tien HY, McMasters KM, Edwards MJ, Chao C. Sentinel lymph node metastasis in anal melanoma: a case report. Int J Gastrointest Cancer 2002; 32:53.
  112. Perez DR, Trakarnsanga A, Shia J, et al. Locoregional lymphadenectomy in the surgical management of anorectal melanoma. Ann Surg Oncol 2013; 20:2339.
  113. Tchelebi L, Guirguis A, Ashamalla H. Rectal melanoma: epidemiology, prognosis, and role of adjuvant radiation therapy. J Cancer Res Clin Oncol 2016; 142:2569.
  114. Kelly P, Zagars GK, Cormier JN, et al. Sphincter-sparing local excision and hypofractionated radiation therapy for anorectal melanoma: A 20-year experience. Cancer 2011; 117:4747.
  115. Thibault C, Sagar P, Nivatvongs S, et al. Anorectal melanoma--an incurable disease? Dis Colon Rectum 1997; 40:661.
  116. Lian B, Si L, Cui C, et al. Phase II randomized trial comparing high-dose IFN-α2b with temozolomide plus cisplatin as systemic adjuvant therapy for resected mucosal melanoma. Clin Cancer Res 2013; 19:4488.
  117. Shoushtari AN, Bluth MJ, Goldman DA, et al. Clinical features and response to systemic therapy in a historical cohort of advanced or unresectable mucosal melanoma. Melanoma Res 2017; 27:57.
  118. Carvajal RD, Antonescu CR, Wolchok JD, et al. KIT as a therapeutic target in metastatic melanoma. JAMA 2011; 305:2327.
  119. Curtin JA, Busam K, Pinkel D, Bastian BC. Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol 2006; 24:4340.
  120. Ugurel S, Hildenbrand R, Zimpfer A, et al. Lack of clinical efficacy of imatinib in metastatic melanoma. Br J Cancer 2005; 92:1398.
  121. Wyman K, Atkins MB, Prieto V, et al. Multicenter Phase II trial of high-dose imatinib mesylate in metastatic melanoma: significant toxicity with no clinical efficacy. Cancer 2006; 106:2005.
  122. Kim KB, Eton O, Davis DW, et al. Phase II trial of imatinib mesylate in patients with metastatic melanoma. Br J Cancer 2008; 99:734.
  123. Hodi FS, Friedlander P, Corless CL, et al. Major response to imatinib mesylate in KIT-mutated melanoma. J Clin Oncol 2008; 26:2046.
  124. Lutzky J, Bauer J, Bastian BC. Dose-dependent, complete response to imatinib of a metastatic mucosal melanoma with a K642E KIT mutation. Pigment Cell Melanoma Res 2008; 21:492.
  125. Guo J, Si L, Kong Y, et al. Phase II, open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification. J Clin Oncol 2011; 29:2904.
  126. Hodi FS, Corless CL, Giobbie-Hurder A, et al. Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sun-damaged skin. J Clin Oncol 2013; 31:3182.
  127. Carvajal RD, Lawrence DP, Weber JS, et al. Phase II Study of Nilotinib in Melanoma Harboring KIT Alterations Following Progression to Prior KIT Inhibition. Clin Cancer Res 2015; 21:2289.
  128. Lee SJ, Kim TM, Kim YJ, et al. Phase II Trial of Nilotinib in Patients With Metastatic Malignant Melanoma Harboring KIT Gene Aberration: A Multicenter Trial of Korean Cancer Study Group (UN10-06). Oncologist 2015; 20:1312.
  129. Guo J, Carvajal RD, Dummer R, et al. Efficacy and Safety of Nilotinib in Patients With KIT-Mutated Metastatic or Inoperable Melanoma: Final Results From the Global, Single-Arm, Phase II TEAM Trial. Ann Oncol 2017.
  130. Quintás-Cardama A, Lazar AJ, Woodman SE, et al. Complete response of stage IV anal mucosal melanoma expressing KIT Val560Asp to the multikinase inhibitor sorafenib. Nat Clin Pract Oncol 2008; 5:737.
  131. Kalinsky K, Lee S, Rubin KM, et al. A phase 2 trial of dasatinib in patients with locally advanced or stage IV mucosal, acral, or vulvovaginal melanoma: A trial of the ECOG-ACRIN Cancer Research Group (E2607). Cancer 2017; 123:2688.
  132. Zhu Y, Si L, Kong Y, et al. Response to sunitinib in Chinese KIT-mutated metastatic mucosal melanoma. J Clin Oncol 2009; 27S: ASCO #e20017.
  133. Postow MA, Luke JJ, Bluth MJ, et al. Ipilimumab for patients with advanced mucosal melanoma. Oncologist 2013; 18:726.
  134. Del Vecchio M, Di Guardo L, Ascierto PA, et al. Efficacy and safety of ipilimumab 3mg/kg in patients with pretreated, metastatic, mucosal melanoma. Eur J Cancer 2014; 50:121.
  135. Shoushtari AN, Munhoz RR, Kuk D, et al. The efficacy of anti-PD-1 agents in acral and mucosal melanoma. Cancer 2016; 122:3354.
  136. D'Angelo SP, Larkin J, Sosman JA, et al. Efficacy and Safety of Nivolumab Alone or in Combination With Ipilimumab in Patients With Mucosal Melanoma: A Pooled Analysis. J Clin Oncol 2017; 35:226.
  137. Hamid O, Robert C, Ribas A, et al. Antitumour activity of pembrolizumab in advanced mucosal melanoma: a post-hoc analysis of KEYNOTE-001, 002, 006. Br J Cancer 2018; 119:670.
  138. Nathan P, Ascierto PA, Haanen J, et al. Safety and efficacy of nivolumab in patients with rare melanoma subtypes who progressed on or after ipilimumab treatment: a single-arm, open-label, phase II study (CheckMate 172). Eur J Cancer 2019; 119:168.
  139. Kim KB, Sanguino AM, Hodges C, et al. Biochemotherapy in patients with metastatic anorectal mucosal melanoma. Cancer 2004; 100:1478.
  140. Harting MS, Kim KB. Biochemotherapy in patients with advanced vulvovaginal mucosal melanoma. Melanoma Res 2004; 14:517.
  141. Bartell HL, Bedikian AY, Papadopoulos NE, et al. Biochemotherapy in patients with advanced head and neck mucosal melanoma. Head Neck 2008; 30:1592.
  142. Smyth EC, Flavin M, Pulitzer MP, et al. Treatment of locally recurrent mucosal melanoma with topical imiquimod. J Clin Oncol 2011; 29:e809.
  143. Hyde MA, Hadley ML, Tristani-Firouzi P, et al. A randomized trial of the off-label use of imiquimod, 5%, cream with vs without tazarotene, 0.1%, gel for the treatment of lentigo maligna, followed by conservative staged excisions. Arch Dermatol 2012; 148:592.
  144. Bong AB, Bonnekoh B, Franke I, et al. Imiquimod, a topical immune response modifier, in the treatment of cutaneous metastases of malignant melanoma. Dermatology 2002; 205:135.
  145. Wolf IH, Smolle J, Binder B, et al. Topical imiquimod in the treatment of metastatic melanoma to skin. Arch Dermatol 2003; 139:273.
  146. Naylor MF, Crowson N, Kuwahara R, et al. Treatment of lentigo maligna with topical imiquimod. Br J Dermatol 2003; 149 Suppl 66:66.
  147. Powell AM, Robson AM, Russell-Jones R, Barlow RJ. Imiquimod and lentigo maligna: a search for prognostic features in a clinicopathological study with long-term follow-up. Br J Dermatol 2009; 160:994.
  148. Sheng X, Yan X, Chi Z, et al. Overall survival and biomarker analysis of a phase Ib combination study of toripalimab, a humanized IgG4 mAb against programmed death-1 (PD-1) with axitinib in patients with metastatic mucosal melanoma. J Clin Oncol 2020; 38:15S.
Topic 16904 Version 41.0

References

1 : 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.

2 : Head and neck mucosal melanoma: experience with 42 patients, with emphasis on the role of postoperative radiotherapy.

3 : Primary malignant melanoma of the oral cavity. A review of 177 cases.

4 : Patient characteristics, methods of diagnosis, and treatment of mucous membrane melanoma in the United States of America.

5 : Primary malignant melanoma of the mucous membranes.

6 : Primary mucosal melanoma.

7 : Incidence of noncutaneous melanomas in the U.S.

8 : Incidence of cutaneous melanoma among non-Hispanic whites, Hispanics, Asians, and blacks: an analysis of california cancer registry data, 1988-93.

9 : Mucosal melanoma of the female genital tract is a multifocal disorder.

10 : Mucosal melanoma: a clinically and biologically unique disease entity.

11 : Malignant melanoma of the skin of the head and neck. An analysis of 405 cases.

12 : Prognosis of Mucosal, Uveal, Acral, Nonacral Cutaneous, and Unknown Primary Melanoma From the Time of First Metastasis.

13 : Malignant mucosal melanoma of the head and neck: review of the literature and report of 14 patients.

14 : Mucosal melanoma of the head and neck.

15 : Primary mucosal malignant melanoma of the head and neck.

16 : Primary mucosal melanoma of the head and neck. Comparison of clinical presentation and histopathologic features of oral and sinonasal melanoma.

17 : Malignant melanoma of the mucous membranes: a review of 119 cases.

18 : Mucosal melanomas of the head and neck: experience of the Princess Margaret Hospital.

19 : Primary malignant melanoma of the pharynx.

20 : Primary malignant melanoma of the larynx.

21 : Primary malignant melanoma of the esophagus.

22 : Endoscopic and pathologic findings associated with clinical outcomes of melanoma in the upper gastrointestinal tract.

23 : Mucosal melanoma of the head and neck.

24 : Mucosal melanoma of the head and neck: the impact of local control on survival.

25 : Mucosal melanoma of the nose and paranasal sinuses, a contemporary experience from the M. D. Anderson Cancer Center.

26 : Mucosal melanoma of the nose and paranasal sinuses, a contemporary experience from the M. D. Anderson Cancer Center.

27 : Primary mucosal melanoma of the head and neck: a proposal for microstaging localized, Stage I (lymph node-negative) tumors.

28 : Sinonasal tract and nasopharyngeal melanomas: a clinicopathologic study of 115 cases with a proposed staging system.

29 : Head and neck mucosal melanoma: The United Kingdom national guidelines.

30 : Craniofacial resection for malignant melanoma of the skull base: report of an international collaborative study.

31 : Management options and survival in malignant melanoma of the sinonasal mucosa.

32 : Endoscopic resection of sinonasal cancers with and without craniotomy: oncologic results.

33 : Melanoma of the upper aerodigestive tract: a review of 21 cases.

34 : Radiotherapy in the treatment of mucosal melanoma of the upper aerodigestive tract: analysis of 74 cases. A Rare Cancer Network study.

35 : Head and neck mucosal melanoma: a 32-year review.

36 : Current management of mucosal melanoma of the head and neck.

37 : Sentinel lymph node biopsy: A new perspective in head and neck mucosal melanoma?

38 : Radioguided surgical strategy in mucosal melanoma of the nasal cavity.

39 : The role of postoperative adjuvant radiation therapy in the treatment of mucosal melanomas of the head and neck region.

40 : Postoperative adjuvant radiation therapy in the treatment of primary head and neck mucosal melanomas.

41 : Postoperative radiotherapy for primary mucosal melanoma of the head and neck.

42 : Postoperative radiotherapy in head and neck mucosal melanoma: a GETTEC study.

43 : Mucosal malignant melanoma of the head and neck: the Marsden experience over half a century.

44 : Adjuvant radiotherapy in sinonasal mucosal melanoma: A retrospective analysis.

45 : The effectiveness of radiotherapy in the treatment of head and neck mucosal melanoma: Systematic review and meta-analysis.

46 : Radiotherapy after surgical resection for head and neck mucosal melanoma.

47 : A multi-institutional retrospective analysis of external radiotherapy for mucosal melanoma of the head and neck in Northern Japan.

48 : Multicenter Study of Carbon-Ion Radiation Therapy for Mucosal Melanoma of the Head and Neck: Subanalysis of the Japan Carbon-Ion Radiation Oncology Study Group (J-CROS) Study (1402 HN).

49 : Toward a better understanding of sinonasal mucosal melanoma: clinical review of 23 cases.

50 : Sinonasal melanoma: a clinicopathologic review of 61 cases.

51 : Localized sinonasal mucosal melanoma: Outcomes and associations with stage, radiotherapy, and positron emission tomography response.

52 : Primary malignant melanoma of the urethra.

53 : Primary malignant melanoma of the urinary bladder.

54 : Primary malignant melanoma of the urinary bladder diagnosed by urine cytology: a case report.

55 : Primary malignant melanoma of the uterine cervix: case report with world literature review.

56 : Primary malignant melanoma of the uterine cervix: case report and review of the literature.

57 : A survey of hospital management practices for vulvar melanoma.

58 : Population-based incidence rates of malignant melanoma of the vulva in Germany.

59 : Malignant melanoma of the vulva in a nationwide, 25-year study of 219 Swedish females: clinical observations and histopathologic features.

60 : Vulvar melanoma: a report of 20 cases and review of the literature.

61 : Malignant melanoma of the vulva: a clinicopathologic study of 18 cases.

62 : Malignant melanoma of the vulva: report of six cases and review of the literature.

63 : Vulvar melanoma at the M. D. Anderson Cancer Center: 25 years later.

64 : Primary malignant melanoma of the vagina: case report and review of literature.

65 : Vulvar melanoma: a multivariable analysis of 644 patients.

66 : Primary malignant melanoma of the vagina: a clinicopathological analysis of 10 cases.

67 : Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma.

68 : The histogenesis and biologic behavior of primary human malignant melanomas of the skin.

69 : Thickness, cross-sectional areas and depth of invasion in the prognosis of cutaneous melanoma.

70 : Malignant melanoma of the vulva: A report of 44 cases.

71 : Malignant melanoma of the vulva treated by radical hemivulvectomy. A prospective study of the Gynecologic Oncology Group.

72 : Malignant melanoma of the vulva: an extension of cutaneous melanoma?

73 : Melanoma of the vulva and vagina: principles of staging and their relevance to management based on a clinicopathologic analysis of 85 cases.

74 : Primary vaginal melanoma: thirteen-year disease-free survival after wide local excision and review of recent literature.

75 : Primary malignant melanoma of the vagina: long-term remission following radiation therapy.

76 : Vulvar melanoma: a retrospective analysis and literature review.

77 : Melanomas of the vulva and vagina.

78 : Mucosal melanoma of the female genitalia: a clinicopathologic study of forty-three cases at Duke University Medical Center.

79 : Malignant melanoma of the vulva in a nationwide, 25-year study of 219 Swedish females: predictors of survival.

80 : Primary vaginal melanoma: a critical analysis of therapy.

81 : Management of vulvar melanoma and review of the literature.

82 : Malignant melanoma of the vulva: a clinicopathological study of 50 women.

83 : Management of vulvar melanoma.

84 : Malignant melanoma of the vagina and locoregional control: radical surgery revisited.

85 : Vulvar melanoma: is there a role for sentinel lymph node biopsy?

86 : Utility of sentinel node biopsy in vulvar and vaginal melanoma: report of two cases and review of the literature.

87 : Malignant melanoma of the vulva.

88 : Primary malignant melanoma of the vagina: a case report and review of the current treatment options.

89 : The management of vaginal melanoma.

90 : Malignant melanoma of the vulva and vagina in the United States: patterns of incidence and population-based estimates of survival.

91 : The National Cancer Data Base report on cancer of the vagina.

92 : Primary malignant melanoma of the vagina.

93 : Changing epidemiology of anorectal melanoma.

94 : Primary melanomas of the esophagus and anorectum: epidemiologic comparison with melanoma of the skin.

95 : Incidence and risk factors for the occurrence of non-AIDS-defining cancers among human immunodeficiency virus-infected individuals.

96 : Anal versus rectal melanoma: does site of origin predict outcome?

97 : Practice patterns and outcomes for anorectal melanoma in the USA, reviewing three decades of treatment: is more extensive surgical resection beneficial in all patients?

98 : Surgical management of primary anorectal melanoma.

99 : Malignant melanoma of the anus: report of 12 patients and analysis of 255 additional cases.

100 : Epidemiology and prognosis of anorectal melanoma.

101 : Anorectal malignant melanoma in Sweden. Report of 49 patients.

102 : Patterns of failure in anorectal melanoma. A guide to surgical therapy.

103 : Anal melanoma.

104 : Anorectal melanoma. A 64-year experience at Memorial Sloan-Kettering Cancer Center.

105 : The role of abdominoperineal resection as surgical therapy for anorectal melanoma.

106 : Sphincter-sparing local excision and adjuvant radiation for anal-rectal melanoma.

107 : Abdominoperineal resection provides better local control but equivalent overall survival to local excision of anorectal malignant melanoma: a systematic review.

108 : Anorectal melanoma in The Netherlands: a report of 63 patients.

109 : Importance of clear resection margins in anorectal malignant melanoma.

110 : Wide local excision or abdominoperineal resection as the initial treatment for anorectal melanoma?

111 : Sentinel lymph node metastasis in anal melanoma: a case report.

112 : Locoregional lymphadenectomy in the surgical management of anorectal melanoma.

113 : Rectal melanoma: epidemiology, prognosis, and role of adjuvant radiation therapy.

114 : Sphincter-sparing local excision and hypofractionated radiation therapy for anorectal melanoma: A 20-year experience.

115 : Anorectal melanoma--an incurable disease?

116 : Phase II randomized trial comparing high-dose IFN-α2b with temozolomide plus cisplatin as systemic adjuvant therapy for resected mucosal melanoma.

117 : Clinical features and response to systemic therapy in a historical cohort of advanced or unresectable mucosal melanoma.

118 : KIT as a therapeutic target in metastatic melanoma.

119 : Somatic activation of KIT in distinct subtypes of melanoma.

120 : Lack of clinical efficacy of imatinib in metastatic melanoma.

121 : Multicenter Phase II trial of high-dose imatinib mesylate in metastatic melanoma: significant toxicity with no clinical efficacy.

122 : Phase II trial of imatinib mesylate in patients with metastatic melanoma.

123 : Major response to imatinib mesylate in KIT-mutated melanoma.

124 : Dose-dependent, complete response to imatinib of a metastatic mucosal melanoma with a K642E KIT mutation.

125 : Phase II, open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification.

126 : Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sun-damaged skin.

127 : Phase II Study of Nilotinib in Melanoma Harboring KIT Alterations Following Progression to Prior KIT Inhibition.

128 : Phase II Trial of Nilotinib in Patients With Metastatic Malignant Melanoma Harboring KIT Gene Aberration: A Multicenter Trial of Korean Cancer Study Group (UN10-06).

129 : Efficacy and Safety of Nilotinib in Patients With KIT-Mutated Metastatic or Inoperable Melanoma: Final Results From the Global, Single-Arm, Phase II TEAM Trial.

130 : Complete response of stage IV anal mucosal melanoma expressing KIT Val560Asp to the multikinase inhibitor sorafenib.

131 : A phase 2 trial of dasatinib in patients with locally advanced or stage IV mucosal, acral, or vulvovaginal melanoma: A trial of the ECOG-ACRIN Cancer Research Group (E2607).

132 : Response to sunitinib in Chinese KIT-mutated metastatic mucosal melanoma

133 : Ipilimumab for patients with advanced mucosal melanoma.

134 : Efficacy and safety of ipilimumab 3mg/kg in patients with pretreated, metastatic, mucosal melanoma.

135 : The efficacy of anti-PD-1 agents in acral and mucosal melanoma.

136 : Efficacy and Safety of Nivolumab Alone or in Combination With Ipilimumab in Patients With Mucosal Melanoma: A Pooled Analysis.

137 : Antitumour activity of pembrolizumab in advanced mucosal melanoma: a post-hoc analysis of KEYNOTE-001, 002, 006.

138 : Safety and efficacy of nivolumab in patients with rare melanoma subtypes who progressed on or after ipilimumab treatment: a single-arm, open-label, phase II study (CheckMate 172).

139 : Biochemotherapy in patients with metastatic anorectal mucosal melanoma.

140 : Biochemotherapy in patients with advanced vulvovaginal mucosal melanoma.

141 : Biochemotherapy in patients with advanced head and neck mucosal melanoma.

142 : Treatment of locally recurrent mucosal melanoma with topical imiquimod.

143 : A randomized trial of the off-label use of imiquimod, 5%, cream with vs without tazarotene, 0.1%, gel for the treatment of lentigo maligna, followed by conservative staged excisions.

144 : Imiquimod, a topical immune response modifier, in the treatment of cutaneous metastases of malignant melanoma.

145 : Topical imiquimod in the treatment of metastatic melanoma to skin.

146 : Treatment of lentigo maligna with topical imiquimod.

147 : Imiquimod and lentigo maligna: a search for prognostic features in a clinicopathological study with long-term follow-up.

148 : Overall survival and biomarker analysis of a phase Ib combination study of toripalimab, a humanized IgG4 mAb against programmed death-1 (PD-1) with axitinib in patients with metastatic mucosal melanoma.