Mucosal Melanomas of the Oral Cavity: A Tertiary Care Centre Experience of Surgically Treated Cases

Abstract

Mucosal melanoma of oral cavity (MMO) is a relatively rare tumour comprising of 40% of all head and neck mucosal melanomas. This study assessed the treatment outcomes and factors affecting prognosis in oral cavity mucosal melanomas. The clinical case records of 25 cases of oral cavity mucosal melanomas treated in our institution during 2003–2013 were retrospectively reviewed. Various clinicopathological parameters were taken into consideration and statistical analysis done by Kaplan–Meier method and Cox’s proportional hazards model. The most common sites of MMO were upper alveolus and hard palate (64%) followed by lower alveolus (28%). 57.1% mucosal melanomas of hard palate and upper alveolus had associated metastatic lymph nodes whereas all cases of MMO of lower alveolus had lymph node metastasis. Disease failure at distant sites was higher than that at primary site or lymph nodes. The most common site of distant metastases was brain. The 5-year OS for treated cases was 23.8% and among subsites, MMO of hard palate and upper alveolus had the highest survival. Metastasis to lymph nodes and bone infiltration by tumour significantly decreased the survival. Recurrence at primary site had the worst prognosis. MMO with lymph nodal involvement and bone erosion had poor prognosis. Due to high chances of lymph node metastases and disease recurrence in lymph nodes following treatment, it is essential to do an elective neck dissection for all cases of MMO. Disease failure at primary site was an independent predictor of outcome in MMO.

Introduction

Mucosal melanoma constitutes to less than 1% of all melanomas. 55% of mucosal melanomas arise in the head and neck region [1]. Mucosal melanoma is a rare tumour of the oral cavity with a very poor prognosis. Mucosal melanoma of oral cavity (MMO) constitutes 40% of all head and neck mucosal melanomas. Among the subsites of oral cavity, majority of MMO occur in the upper alveolus and hard palate (70%) followed by lower alveolus [2].

MMO present as painless pigmented lesions in mucosa which are incidentally detected. MMO are diagnosed at an early stage as compared to mucosal melanomas in other head and neck subsites like nose and paranasal sinuses. The challenges that the oncologists face while treating MMO are that no adjuvant treatment has shown any promising outcomes and the poor prognosis associated with this malignancy.

Materials and Methods

This is a retrospective study done in our institution, one among the leading cancer centres in the country. The purpose of this study was to assess the treatment outcomes and the factors determining the prognosis of MMO. Clinical case records of all cases treated in our institution from 2004 to 2013 were reviewed. There were 25 cases treated during this period involving the buccal mucosa, upper alveolus, hard palate and lower alveolus. Immunohistochemistry had a significant role in clinching the diagnosis of mucosal melanoma during histopathology evaluation.

All patients had a computed tomography (CT) or magnetic resonance imaging (MRI) done for evaluation of the disease. CT scan identifies bone erosion and MRI aids in assessing soft tissue involvement. FDG avidity of mucosal melanomas makes Positron Emission Tomography (PET) an important investigation to rule out distant metastasis and disease recurrence. PET scan was done to rule out distant metastasis as part of work-up.

Since AJCC Cancer Staging Manual 8th Edition has described only advanced T staging and there is no prognostic stage grouping for classifying mucosal melanomas, many authors including us prefer a practical staging system that categorizes mucosal melanomas into the following: Stage I—localized disease, Stage II—regional metastases and Stage III—distant metastases.

All cases were managed as per institutional protocol. Surgery was done for 21 cases of the 25 cases. Intra-operative frozen section facility was utilized to ensure adequate margins during surgical resection. Post-operative adjuvant treatment was considered for cases with lymph node metastases or advanced primary disease involving bone.

The various parameters taken into consideration in this study included subsite of oral cavity involved, stage at intial presentation, clinical features, immunohistochemistry, treatment, final histopathology and follow-up data including interval of recurrence and survival. 5-year overall survival (OS) and disease specific survival (DSS) were calculated using Kaplan–Meier method and univariate comparisons of survival was done using log rank test. The prognostic factors were assessed by Cox’s proportional hazards model.

Results

There were 25 cases of mucosal melanoma of oral cavity (MMO) included in this study. Age of initial presentation of MMO cases ranged from 24 to 81 years of age with a mean age of 52.1 years. Among them, 64% of cases were more than 50 years of age with a male preponderance (M:F = 56%:44%). 28% of cases presented in stage I, 56% of cases presented in stage II and 16% presented in stage III of the disease.

The most common sites of MMO were upper alveolus and hard palate (64%) followed by lower alveolus (28%) (Fig. 1). 88% of cases with MMO presented with complaints of pigmented lesion in the mucosa of oral cavity. 44% of MMO had clinical and radiological evidence of bone involvement. Immunohistochemistry was done for all cases and showed positivity of S100 and HMB45 in 92% cases. Metastatic workup for all cases which underwent surgery was negative.

Fig. 1.

Site of origin of mucosal melanoma in oral cavity

Twenty one cases underwent surgery in our institution followed by adjuvant radiation treatment in indicated cases. Remaining four cases had distant metastases at initial presentation and underwent palliative treatment. 64% of surgically treated cases underwent post-operative adjuvant radiotherapy, the total dose of radiation received varied between 50 and 66 Gy in 25–33 fractions. The median follow-up period was 74 months, with a maximum follow-up of 9 years and a minimum follow-up of 41 months.

Surgical resection of the primary lesion was complete in all cases. Margin clearance achieved on intra-operative frozen section was confirmed on final histopathology. Neck dissection was done for 15 among the 21 cases and among them 93% of cases had lymph node metastasis in final histopathology. 57.1% mucosal melanomas of hard palate and upper alveolus had associated metastatic lymph nodes whereas all 100% cases of lower alveolus cases had lymph node metastasis.

Among the 16 cases of MMO which had disease failure following curative treatment, the rate of disease failure at distant sites was highest at 47.6% compared to primary site recurrence (23.8%) and nodal recurrence (23.8%). The most common sites of distant metastases were brain followed by lung and liver (Table 1). The median time interval of recurrence was 11 months.

Table 1.

Distant failure of disease following curative treatment

Most common sites of distant metastasis
	Frequency	Percent
Brain	4	40.0
Lung	3	30.0
Liver	2	20.0
Pancreas	1	10.0
Total	10	100.0

The 5-year OS for 21 cases which underwent surgery was 23.8%. Considering the subsites, 5-year OS was highest for hard palate and upper alveolus followed by lower alveolus (Table 2). Among the 21 cases of MMO who underwent surgery, only 2 patients are presently alive and disease-free.

Table 2.

Overall survival for surgically treated cases based on most commonly involved subsites

Subsite	Alive	Death	5 year survival probability (%)
Buccal mucosa	0	1	0.0
Hard palate& Upper alveolus	2	12	21.4
Lower alveolus	0	6	33.3

The 5-year DSS was 28.4% for surgically treated cases. Metastasis to lymph nodes confirmed on final histopathology decreased the 5-year DSS to 24.1%, whereas in cases without lymph node metastasis the 5-year DSS was 40% (Fig. 2). Similarly bone infiltration by tumour on final histopathology also significantly decreased DSS by 29.1% (Table 3). There was no significant survival advantage for patients who received post-operative radiotherapy.

Fig. 2.

5-year Disease specific survival associated with lymph node metastasis

Table 3.

Disease specific survival of surgically treated cases

Bone erosion	Alive	Dead	5 year disease specific survival (%)
Present	1	7	12.5
Absent	4	9	41.6

In case of disease recurrence, the 5-year DSS was lowest for cases which had primary site recurrence (0%) compared to distant recurrence (11.3%) and lymph nodal recurrence (20%). Disease failure at primary site had a significant correlation with DSS (p value 0.013) (Table 4). The 5-year DSS of patients in stage I and stage II of the disease were 40% and 24.1%. Whereas none of the patients in stage III of disease survived beyond 2 years.

Table 4.

Association of disease failure at primary site and survival

Recurrence at primary site	Alive	Dead	5 year disease specific survival (%)	Std. error (%)	P-value
Present	0	5	0.0	0.0	0.013
Absent	5	11	39.2	13.6

Discussion

The etiological factors causing mucosal melanomas are not clearly understood. Melanocytes, the precursor cells for mucosal melanoma have been extensively identified in the mucous membranes of such cases. Two benign pigmented lesions of the oral cavity which can mimic mucosal melanoma are melanotic macule and intramucosal naevus. These are pigmented lesions seen in the oral cavity which have well-defined specific histopathological criteria and need to be differentiated from mucosal melanomas [3].

According to the TNM staging of mucosal melanomas, T1 and T2 lesions are omitted due to poor prognosis associated with superficial lesions. Hence staging starts from T3 for lesions confined to mucosa and adjacent soft tissue and T4 for moderately advanced and very advanced lesions.

MMO is a disease of the elderly usually seen in individuals between fifth and the eighth decade of life and with a male preponderance. In our study 64% of patients were over 50 years of age and 57% of them were males. In the systemic review by Nandapalan et al., the most common oral cavity subsites were hard palate and upper alveolus (80%) [3]. Similarly the most common subsite in our study was hard palate and upper alveolus (64%).

On histology melanocytes have polyhedral to pleomorphic shapes with prominent mitotic activity. Confirmation is usually with immunohistochemistry using S100, melanocyte markers like MART 1/Melan A, tyrosinase, HMB45 and MITF. Among them S100 has highest sensitivity and HMB45 has the maximum specificity. In our study, 88% of cases showed positivity to S100 & HMB45.

Oral mucosal melanomas present with pigmented macular or papular lesions in the mucosa of oral cavity. About 40% of MMO may be amelanotic. Satellite lesions in oral mucosal melanomas are common. MMOs have higher rates of cervical lymph node metastasis as compared to other head and neck subsites like nose and paranasal sinuses. According to studies by both Chaudhry et al. [4] and Umeda et al. [5], more than 50% of cases of MMO had metastasis to lymph nodes. In our case series, 66.7% MMOs showed metastasis to lymph nodes. Hence it is essential to do an elective neck dissection for all cases of oral cavity mucosal melanomas.

Chaudhry et al. in their study concluded that 20% of MMO cases had distant metastasis at initial presentation [4] which was similar to our case series (16%). According to O’Regen et al., the most common sites of distant metastasis from mucosal melanomas were lungs and liver [6], however in our series the most common site of distant metastasis was brain followed by lungs and liver.

Surgery remains the mainstay of treatment. Though mucosal melanomas were deemed radioresistant, radiotherapy is considered useful as post-operative adjuvant treatment in advanced stages of the disease [7, 8]. For staging of mucosal melanomas based on American Joint Committee on Cancer (AJCC), the National Comprehensive Cancer Network (NCCN) recommends post-operative radiotherapy for stage III confined to the mucosa disease whereas local radiation has definite survival benefit in stage IVA mucosal melanomas with local invasion. Stage IVB which denotes extensive local invasion and stage IVC denotes distant metastases and palliation is ideal treatment [9]. Chemotherapy has a role only in palliative setting.

In our study, 74% of patients underwent post-operative adjuvant radiation for indications of bone infiltration and lymph node involvement. Post-operative radiotherapy improves locoregional disease control without any significant survival advantage according to Nandapalan et al. [3]. In the systemic review by Medenhall et al., they suggested that better locoregional control could be achieved when surgery was combined with radiotherapy as compared to single modality treatment [10]. However in our study post-operative adjuvant radiotherapy did not add any significant survival benefit when compared to cases which did not receive adjuvant radiation.

Even unresectable tumours are now treated with newer modalities like neutron and proton therapies achieving better local control with acceptable toxicities. Systemic therapy with immunomodulators like IFN alpha, Interleukin-2 [11–13] and cKIT inhibitors such as imatinib, sorafenib, dasatinib, or sunitinib are used to treat distant metastasis, however further studies need to be done to establish their efficacy [10, 14, 15].

The 5-year OS for MMO according to various studies is around 12% [2, 16, 17] whereas 5-year OS in our study is around 23.1%. The 5-year DSS in the study by Patel et al. was 40% [2], whereas in our study the 5-year DSS was 28.4%. In the same study the rates of local failure, nodal failure and distant failure were 51%, 42% and 67% respectively. In our study though the rate of distant failure was comparable at 47.6%, however the rate of local and regional failures were much lesser at 23.8%. In 76.2% of surgically treated cases in our case series, the cause of death was either locoregional recurrence or recurrence at distant sites. Presence of metastatic cervical lymph nodes significantly decreased the DSS by 16%.

Conclusions

MMO with lymph nodal involvement and bone erosion have poor prognosis. Mucosal melanomas of the lower alveolus have higher chance of cervical lymph nodal metastasis as compared to other oral cavity subsites. Due to high chances of lymph node metastases and disease recurrence in lymph nodes following treatment, it is essential to do an elective neck dissection during surgery for all cases of MMO. Disease recurrence occurred in less than 1 year following treatment. In MMO the highest chance of disease failure is at distant sites as compared to primary site and regional lymph nodes. Disease failure at primary site was an independent predictor of outcome in MMO.

Abbreviations

MMO

Mucosal melanoma of oral cavity

CT

Computed tomography

MRI

Magnetic resonance imaging

PET

Positron emission tomography

FDG

Fluorodeoxy glucose

OS

Overall survival

DSS

Disease specific survival

AJCC

American Joint Committee on Cancer

NCCN

National Comprehensive Cancer Network

Funding

There was no funding for this research work.

Compliance With Ethical Standards

Conflict of interest

The author declare that there are no conflicts of interest in this research study.

Ethical Approval

All procedures performed in studies were in accordance with the ethical standards of Regional Cancer Centre, Thiruvananthapuram approved by the Institutional Ethics Committee.

Informed Consent

The author agrees to publish this article.