Mucosal melanoma

From Clinical Guidelines Wiki


Background

Melanomas arising from mucosal surfaces are very rare tumours and on the whole have a very poor prognosis. The commonest sites are the vulva including vagina, the anus and the upper aero-digestive tract. Several features distinguish mucosal melanoma from cutaneous melanoma including the almost complete absence of BRAF mutations. Up to one third of mucosal melanomas of the vagina and anus overexpress the receptor kinase c-kit (compared with less than 5% of cutaneous melanomas) which has implications for treatment with imatinib. [1] However, these mutations are rarely seen in sino-nasal melanoma.[2] There is limited experience with the use of immunotherapy in advanced mucosal melanoma but in general, response rates and duration of response are considerably less than seen with cutaneous melanoma.[3] Patients with mucosal melanoma should be strongly considered for referral to a major centre with experience in the management of these tumours.

Given the significant risk of distant disease at the time of presentation with these tumours, patients are recommended to undergo staging with PET-CT or CT scanning as well as imaging of the brain (MRI or CT scan).

All patients with tumours indicating a significant risk of recurrence should have molecular studies at the time of diagnosis (c-kit).

Currently adjuvant systemic therapy is not recommended for patients with mucosal melanoma. Given the rarity of the disease, treatment algorithms based on experience with cutaneous melanoma may become available in the future. Patients with evidence of disseminated disease should be referred to a unit experienced in the management of melanoma for consideration of targeted therapies (eg imatinib) or immunotherapy.[3][4]

There is no level I or randomised evidence to guide the management of these tumours due to their rarity and recommendations are consensus-based only.

Melanomas of the conjunctiva and uveal tract are considered in the Ocular melanoma section of these guidelines.

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Melanoma of the anorectal region

Anorectal melanoma (ARM) is a rare condition accounting for less than 1% of anorectal tumours. The rate appears to be similar for patients of different racial and ethnic backgrounds. The median age of onset is approximately 60 years, with a slight female preponderance. The common presenting symptoms are haemorrhoidal-type bleeding, a mass or discomfort. Most series report that at least a third of ARMs are excised with a preoperative diagnosis of haemorrhoids. The characteristic appearance is of a polypoid lesion, frequently ulcerated, although sessile and flat lesions are also encountered. Most lesions appear to arise around the dentate line or below it in the anal canal. A small proportion of lesions appear to arise from the rectal mucosa just above the dentate line. Melanomas occurring in normal skin outside the anal canal should be considered as cutaneous melanoma and treated accordingly. Although microscopically it appears that the majority of ARMs contain melanin, at least a quarter and possibly a greater percentage do not contain obvious melanin macroscopically, so that many ARMs do not have the typical dark appearance of cutaneous melanoma.

At least 20% of patients will present with regional lymph node metastases. Another 20–40% will have distant metastatic disease at the time of presentation. The average tumour size is in the order of 3–4cm and there is often associated in situ change. The standard AJCC/UICC staging for cutaneous melanoma is not appropriate for ARM as most tumours are greater than 4mm in thickness.[5] Tumour thickness has not been shown to be a reliable predictor for ARM nor has the presence of lymph node metastases, histological subtype or gender.

Preoperative evaluation should include staging with PET-CT or CT scan of the chest, abdomen and pelvis. Endoscopic ultrasound to assess the depth of penetration of the tumour to identify patients who may be suitable for a limited procedure has been evaluated in a small number of cases. Back to top

Management of melanoma of the anorectal region

Abdominoperineal resection (APR) was traditionally the mainstay of treatment. In recent years the much lesser procedure of complete wide local excision (WLE) of the primary melanoma with sphincter preservation has been reported.[6][7][8][9][10][11][12][13][14][15][16][17][18][19]

Most but not all studies show a higher rate of local control for patients undergoing APR, but in all but one study no advantage in survival was shown for either APR or local excision. This is an old study from Memorial Sloan Kettering Cancer Center,[20] however a more recent study from the same institution reported very similar rates of local control and overall survival for the two procedures from 1984 to 2003, when the standard of care switched from APR to WLE.[18] Approximately one third of patients with operable (non-metastatic) ARM will require an abdominoperineal excision for complete resection of the melanoma. The extent of margins for either APR or WLE has not been evaluated, although Ward et al aim to achieve a 2cm margin.[21] Remarkably, the width of excision is uncommonly reported in the literature.

Post-operative radiotherapy following WLE has been reported. The largest series from the MD Anderson Cancer Center[22] describes high rates of local and lymph node field control (82% and 88%) and sphincter preservation (96%). However, overall survival was poor (30% at five years) and long-term radiation associated morbidity was frequent (48%).[22]

The commonest site of regional node failure is the inguinal region although the pattern of disease may be related to the primary site (anal canal versus rectum).[23]

Overall survival is not strongly associated with the presence of regional node metastases, most likely reflecting the very high risk of distant metastasis. For this reason, elective inguinal lymphadenectomy not indicated. Sentinel node biopsy has been successfully performed in a small number of cases.[22] In view of the lack of a relationship between outcome and lymph node status and the lack of evidence supporting its use, the role of SNB for ARM remains undefined at the present time.

Lymphadenectomy is indicated for proven regional lymph node involvement at the time of the definitive procedure for primary ARM.

Unfortunately, the majority of patients with ARM will die of the disease, with most manifesting evidence of distant disease within two years of diagnosis. The commonest sites of metastasis are lung (over 50%) followed by liver, brain and gastrointestinal tract. Distant metastatic disease is generally managed similarly to metastatic cutaneous melanoma. Radiotherapy may have a role for palliation of local, regional or distant recurrence.

The overall survival for ARM is poor. Patients with disease confined to the anal canal have a five-year survival of approximately 35% and a median survival of approximately 30 months. Patients with regional disease at presentation have a median survival of 20 months and patients with metastatic disease at presentation rarely survive 12 months. Back to top


Evidence summary Level References
Wide local excision is associated with a higher rate of local recurrence than abdominoperineal resection (APR), but overall no advantage for survival with APR over wide local excision (WLE) has been shown. The very high rate of distant failure and poor overall survival appears to be independent of local recurrence. IV [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18]
Post-operative radiotherapy following WLE results in high rates of local and lymph node field control, but poor overall survival and frequent long-term radiation morbidity. III-2 [22]


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The primary lesion for melanoma of the anorectal region should be managed by sphincter preserving complete local excision in most cases. Abdominoperineal resection is indicated only for patients with loco-regional disease whose primary tumour cannot be resected by a limited procedure.


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The routine use of sentinel node biopsy is not recommended.


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Adjuvant or post-operative radiotherapy after wide local excision may be considered particularly for patients with close/involved margins.


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The care of patients with anorectal melanoma should be undertaken by a multidisciplinary team experienced in the management of these patients.

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Mucosal melanoma of the head and neck

Mucosal melanoma of the head and neck is a very rare tumour accounting for less than 1% of all head and neck melanomas. The median age of presentation is approximately 60 years with a slight male predominance. Approximately 60% occur in the sino-nasal region, with two-thirds arising obviously from the nasal cavity. Virtually all the remainder occur in the oral cavity, particularly the upper jaw apart from a very small percentage found in the larynx.[24]

Nasal melanomas present with nasal obstruction or bloody discharge similar to sinus melanoma. Oral melanoma may present with a mass, an area of pigmentation, bleeding or loosening of teeth. The standard AJCC staging system is not appropriate for mucosal melanoma.[5] Lymph node involvement is unusual at the time of presentation and does not commonly occur among patients who develop local recurrence or distant disease. Back to top

Management of mucosal melanoma of the head and neck

Because of the rarity of this tumour, treatment guidelines are not well established and consideration should be given to referral to a unit with expertise in managing head and neck melanoma. Recommendations for treatment are based on a limited number of small retrospective case series with considerable potential for bias. [24][25][26][27][28][29][30][31][32][33][34][35][36][37]

Complete surgical resection where feasible is recommended. Elective lymphadenectomy for this group of patients who uncommonly present with regional lymphadenopathy is not indicated. The role of sentinel node biopsy is undefined, limited experience to date suggests it may assist in staging and planning of definitive treatment.[38]

Overall survival is poor with reported rates of survival varying from approximately 20% to less than 5% at ten years.[24] A high rate of early haematogenous dissemination and late presentation compared to cutaneous melanoma may explain these poor results.

A number of older studies proposed radiotherapy as definitive treatment but more recent reviews of retrospective data and national databases indicate poor outcomes compared to surgery.[25][29] More recent reports highlight the role of adjuvant post-operative radiotherapy with a significant improvement in local control but without any impact on survival.[27][28][30] Back to top


Evidence summary Level References
Complete surgical excision is the fundamental surgical aim but may be difficult to achieve without a destructive or disabling procedure. The addition of radiotherapy to surgery appears to improve local control but not survival. III-3 [25], [26], [27], [28], [29], [31], [34], [36], [37]
Primary radiotherapy alone has poorer outcomes compared to surgery with or without adjuvant radiotherapy and should be limited to patients unable to undergo surgery. IV [27]
The role of sentinel node biopsy is undefined but may have a role in staging and planning of definitive treatment. IV [38]


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Patients with mucosal melanoma of the head and neck are best managed by complete surgical excision. Adjuvant radiotherapy should be considered particularly for patients with close and or involved margins after surgical resection.


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Patients to be referred to a specialist unit with experience in head and neck melanoma.

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Melanoma of the oesophagus

A very small number of oesophageal melanomas have been reported in the literature, but as the gastro-intestinal tract is a potential site for metastasis from cutaneous melanoma, the true nature of many lesions is debated. Many patients present with disseminated disease. Tumours are often large at presentation and tend to be located in the distal third of the oesophagus. The majority of patients are dead within twelve months. Radical resection can be considered in patients with limited disease.

Radiotherapy may be considered for patients with advanced disease.


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Radical resection can be considered in patients with limited disease.

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Melanoma of the male genito-urinary tract

Melanoma of the male external genitalia and lower urinary tract is very rare. Many patients have been aware of a pre-existing pigmented lesion. Melanomas of the glans penis arise in glabrous skin (no hair follicles or sweat glands) and behave similarly to vulval melanoma. Wide excision rather than penectomy (radical or partial) is appropriate if possible. Lymphadenectomy is indicated for involved inguinal lymph nodes. Sentinel node biopsy has been reported but there is not sufficient evidence to make any recommendation. Overall survival is poor, with most patients dying within three years.

In contrast, melanomas of the skin of the penis and scrotum behave similarly to cutaneous melanoma, but presentation is often delayed and results poorer than seen with cutaneous melanoma. Wide excision is indicated rather than penectomy. Again, a role for SNB has not been established.


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Wide excision is recommended rather than penectomy for melanoma of the glans penis, skin of penis and scrotum.


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The role of SNB is not established for melanoma of the glans penis, skin of penis and scrotum.

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Vulval melanoma

Vulval melanoma is a rare condition accounting for less than 1% of all gynaecological malignancies. In contrast to cutaneous melanoma, the incidence of vulval melanoma appears to be stable or decreasing. It is typically a disease of elderly females (median age at presentation late sixties). Most patients report the presence of a mass and/or bleeding, while pruritus and pain are less common symptoms at presentation.

The commonest histological subtypes are mucosal lentiginous melanoma and nodular melanoma. Many lesions are ulcerated and typically 2–4mm in thickness. The regional lymph nodes are involved in up to one third of patients at presentation, and up to 25% of patients have distant disease at the time of presentation.

The skin of the perineum varies from hair-bearing skin over the labia majora to glabrous (non-hair-bearing skin) in the inner vulva to the mucosa of the vaginal introitus. Up to one third of vulval melanomas arise on the labia majora and are characteristically flat, pigmented lesions, while more centrally-based lesions, which frequently involve the labia minora and clitoris, are characteristically nodular, and up to one third may be amelanonotic. Clark micro-staging is of no value for lesions arising in the mucosa or glabrous skin and Breslow thickness has been variably reported but is of uncertain significance. Most female urogenital melanomas present at an advanced stage hence Breslow tumour thickness is of little prognostic value. The small group of patients with thin melanomas (<1 mm), however, certainly have improved outcomes compared to patients with thicker lesions. Several staging systems have been proposed however the AJCC staging system for cutaneous melanoma appears useful.[5]

Similar to cutaneous melanoma, prognostic factors associated with outcome include tumour thickness, ulceration and lymph node status. In several reports, amelanosis and age were also related to outcome. Overall the prognosis of vulval melanoma is poor, with 50% of patients surviving five years. Five-year survival may be as high as 70% for patients with thin lesions (<1mm) but less than 20% for patients presenting with regional lymph node involvement.[39] Back to top

Management of vulval melanoma

Surgical resection remains the standard of care. There are few prospective data and no randomised studies to guide management due to the rarity of the disease. The surgical approach has evolved from aggressive surgery, for example bilateral vulvectomy with inguinal lymphadenectomy, to more limited procedures due to the recognition that extensive procedures, while providing a higher rate of local control, do not impact on overall survival but cause considerably more morbidity.[40][41][42][43][44][45][46]

Superficial lesions, particularly those in a favourable position, may be treated effectively by wide local excision. Unfortunately central lesions adjacent to the clitoris and urethra, may require more aggressive procedures to obtain complete excision. There is little evidence on which to make recommendations for the width of excision but in principle, for thinner lesions, limited excision margins are appropriate. A Swedish collaborative study reported a series of 281 patients with lesions <2mm thick. The local recurrence rate was 1.8% and was not affected by margin sizes of 1–2cm versus 5cm.[46]

Elective lymph node dissection has not been shown to improve outcome but is associated with considerable morbidity. Sentinel node biopsy has been reported in vulval melanoma but its role is yet to be clarified.[47][48]

The role of adjuvant radiotherapy is undefined but may be considered where resection margins are close. Radiotherapy may have a role for the patient who is unable or unwilling to undergo a surgical procedure or for patients with symptomatic loco-regional recurrence.

Management of distant disease, which has a similar pattern to cutaneous melanoma, should be similar to the management of disseminated cutaneous melanoma. Back to top


Evidence summary Level References
There appears to be no survival advantage to radical procedures over wide excision with modest margins of 1–2cm. There is no survival advantage for prophylactic lymphadenectomy and although sentinel node biopsy has been performed successfully for vulval melanoma, there are little data on its efficacy or safety at the present time. III-3, IV [40], [39], [41], [42], [43], [44], [45], [46], [47], [49], [48]


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Histologically confirmed melanoma of the vulva can be managed by wide excision with limited margins (1–2cm). Extensive lesions particularly those centrally located may require extensive/exenterative procedures. In the absence of proven regional lymph node spread lymphadenectomy is not indicated.


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Patients with vulval melanoma be referred to a specialist unit with expertise.

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Vaginal melanoma

Melanoma of the vagina and urethra is an extraordinarily rare condition. The lower third of the vagina is most commonly affected and patients invariably present with advanced disease. Complete surgical removal, if feasible, frequently requires a major exenterative procedure. The risk of local recurrence, regardless of the extent of surgery or treatment modality, for example radiotherapy, is very high and most patients succumb to a combination of loco-regional and distant disease within a short time.


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Any suspicious lesions of the genital tract should be biopsied.


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As there is a high incidence of systemic disease in these cases, a CT or PET scan is indicated prior to radical surgery.

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References

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