Oral Malignant Melanoma

Overview

Pigmented entities are relatively common in the oral mucosa and arise from intrinsic and extrinsic sources. Conditions such as melanotic macules, nevi, smoker's melanosis, amalgam and graphite tattoos, racial pigmentation, and vascular blood-related pigments occur with some frequency.

Addison disease, Peutz-Jeghers syndrome, and Laugier-Hunziker syndrome also appear in perioral and oral locations as pigmented macules. Addison disease presents as adrenal cortical hypofunction along with splotchy or generalized bronzing of the mucosa and skin. Peutz-Jeghers syndrome has periorificial freckling along with hamartomatous intestinal polyps, and, as a differential diagnosis, Laugier-Hunziker syndrome presents with macular mucocutaneous hyperpigmentation and melanonychia with no known systemic disease association.

Oral pigmentations may range from light brown to blue-black (see the image below), red, or purple. The color depends on the source of the pigment and the depth of the pigment from which the color is derived. Melanin is brown, yet it imparts a blue, green, or brown color to the eye. This effect is due to the depth and density of the pigmented cells (or melanin granule dispersion) and the physical properties of light absorption and reflection described by the Tyndall light phenomenon or effect.

View Image

Photo from a man with an ulcerated, blue-black, slightly elevated lesion in the edentulous, posterior right maxilla. The lesion extends across the res....

Oral conditions with increased melanin pigmentation are common; however, melanocytic hyperplasias or hamartomas are rare. Clinicians must visually inspect the oral cavity, obtain good clinical histories, and be willing to perform a biopsy on any pigmented condition that is not readily explainable or diagnosed. Patients with oral malignant melanoma often recall having an existing oral pigmentation months to years before diagnosis, and the condition may even have elicited prior comment from examining physicians and dentists (or healthcare providers, when considering the auxiliaries).

For more information, see the following:

Malignant Tumors of the Palate
Cancers of the Oral Mucosa
Metastatic Neoplasms to the Oral Cavity
Malignant Tumors of the Floor of the Mouth
Mucosal Melanomas of the Head and Neck
Malignant Melanoma

References

Etiology and Pathophysiology

The cause of oral melanoma or melanoma of any mucosal surface remains unknown, and the incidence has remained stable for more than 25 years. In contrast, cutaneous lesions are linked directly to fair-skinned and blue-eyed persons with a history of blistering sunburns, and the incidence has increased dramatically (approximately 4-6% per year) over the same period. Prognosis regarding the clinical behavior of the mucosal lesions has been extrapolated from knowledge of the cutaneous lesions. However, mucosal exposure to sunlight is unlikely, and, therefore, cutaneous melanoma and mucosal melanoma are different diseases.

The predilection for occurrence in the palate remains a mystery. No link has been established with denture wearing, chemical or physical trauma, or tobacco use. Melanocytic lesions, such as blue nevi, are more common on the palate. Oral blue nevi are not reported to undergo malignant transformation.

Oral melanomas are uncommon (1.2 cases per 10 million population per year in the United States), and, similar to their cutaneous counterparts, they are thought to arise primarily from melanocytes in the basal layer of the squamous mucosa. Melanocytic density has a regional variation. Facial skin has the greatest number of melanocytes. In the oral mucosa, melanocytes are observed in a ratio of about 1 melanocyte to 10 basal cells.

In contrast to cutaneous melanomas, which are etiologically linked to sun exposure, risk factors for mucosal melanomas are unknown. These melanomas have no apparent relationship to chemical, thermal, or physical events (eg, smoking; alcohol intake; poor oral hygiene; irritation from teeth, dentures, or other oral appliances) to which the oral mucosa is constantly exposed. Although benign, intraoral melanocytic proliferations (nevi) occur and are potential sources of some oral melanomas (see the following image); the sequence of events is poorly understood in the oral cavity. Currently, most oral melanomas are thought to arise de novo.

View Image

Photo from a male Japanese patient with extensive, black-pigmented and irregularly bordered macule in the maxillary labial mucosa and midline facial g....

Although rare, malignant transformation of nevi to melanoma involves the clonal expansion of cells that acquire a selective growth advantage. This transformation of melanocytes in an existing nevus, or of single melanocytes in the basal cell layer, must occur before the altered cells proliferate in any dimension.

In cutaneous melanomas, well-known differences exist in the biologic behaviors of the radial growth phase–melanoma (flat or macular), vertical growth phase–melanoma (mass, nodule, elevation), and vertical growth phase–melanoma with metastasis. Some authorities have stated that these different growth patterns require cellular alteration or transformation to progress to the next, more biologically aggressive phase.^[1]Radial growth phase–melanomas do not tend to invade the underlying reticular dermis, but they are associated with metastasis. Vertical growth phase–melanomas, although invasive, must achieve some competence before subsequent metastasis can occur.

Elder et al have described this progression and state that differences in each phase are qualitative.^[1]However, phase progression is not absolute, because most benign melanocytic lesions do not evolve into melanoma. Melanoma development requires a cytogenetic or biochemical alteration in the precursor cells undergoing clonal expansion. This alteration triggers accelerated growth and invasive potential, but not necessarily progression from horizontal to vertical growth phases.

The oral mucosa has an underlying lamina propria, not a papillary and reticular dermis with easily discernible boundaries as observed in skin. This architectural difference obviates the use of Clark levels for describing mucosal melanomas. The term melanoma in situ, once reserved for a cutaneous melanoma that had not breached the basement membrane zone, is now used for mucosal lesions confined to the epithelium (although some authorities prefer the term melanocytic intraepithelial neoplasia for both the cutaneous and mucosal lesions). See Staging.

References

Epidemiology

In contrast to the incidence of cutaneous melanoma, which continues to rise, the incidence of oral melanoma has remained stable for more than 30 years.

Surveillance data in the United States are not available for oral melanoma alone. Data for oral melanoma are included in the combined statistics for oral cancer. In a review of the large studies, melanoma of the oral cavity is reported to account for 0.2-8% of melanomas and approximately 1.6% of all malignancies of the head and neck.^[2] In some studies, primary lesions of the lip and nasal cavity also are included in the statistics, thereby increasing the incidence.

A critical review of the literature by Hicks and Flaitz found that the vast majority of melanomas occur on the skin (91.2%); ocular melanomas account for 5.3%, unknown primary lesions account for 2.2%, and melanomas of the mucous membrane account for 1.3%.^[3]The oral mucosa is primarily involved in less than 1% of melanomas, and the most common locations are the hard palate and maxillary gingiva. Metastatic melanoma most frequently affects the mandible, tongue, and buccal mucosa.

Internationally, oral melanoma is more common in the Japanese than in other groups. This observation is based on a review of frequently cited historical literature. Oral malignant melanoma, although rare in white persons, remains a major cause for concern. In Japan, oral melanomas account for 11-12.4% of all melanomas, and males may be affected slightly more often than females.^[4]This percentage is higher than the 0.2-8% reported in the United States and Europe. Since cutaneous melanoma is less common in more darkly pigmented races, people of these races have a greater relative incidence of oral mucosal melanoma.^[5]

Sex and age differences

The rarity of oral melanoma has led to ambiguity in defining sex predilections, as some studies have stated a decided male predilection while others have shown a slight female predilection.^{[6, 7]}A roughly equal sex distribution of melanoma in the skin exists. In Japan, data suggest an equal or slight male predilection.

Although oral melanoma occurs over a broad age range, it is largely a disease of those older than 40 years, and it is rare in patients younger than 20 years. The average patient age at diagnosis is 56 years. Oral malignant melanoma is commonly diagnosed in men aged 51-60 years, whereas it is commonly diagnosed in women aged 61-70 years.

A separate categorization of "oral mucosal melanoma" in the cancer surveillance data reported in the United States and by the World Health Organization (WHO) would be useful in clarifying race and sex prevalence. Until that clarification occurs, statistics will continue to be derived from case reports and review articles that reflect the observation and opinion of those authors.

References

Clinical Evaluation

Oral melanomas arise silently, with few symptoms until progression has occurred. Most people do not inspect their oral cavity closely, and melanomas are allowed to progress until significant swelling, tooth mobility, or bleeding causes them to seek care. Pigmented lesions 1.0 mm to 1.0 cm or larger are found. Reports of previously existing pigmented lesions are common. These lesions may represent unrecognized melanomas in the radial growth phase.

Amelanotic melanoma accounts for 5-35% of oral melanomas. This melanoma appears in the oral cavity as a white, mucosa-colored, or red mass. The lack of pigmentation contributes to clinical and histologic misdiagnosis. However, the presence of a lymphocytic infiltrate is helpful histopathologically (see Histologic Findings). This host immunologic recognition is most helpful to the pathologist in the diagnosis of both amelanotic and desmoplastic lesions.

Because oral malignant melanomas are often clinically silent, they can be confused with a number of asymptomatic, benign, pigmented lesions. Oral melanomas are largely macular, but nodular and even pedunculated lesions occur. Pain, ulceration, and bleeding are rare in oral melanoma until late in the disease.

On physical examination, the pigmentation of these lesions varies from dark brown to blue-black (see the following image); however, mucosa-colored and white lesions are occasionally noted, and erythema is observed when the lesions are inflamed.

View Image

Large, blue-black, irregularly bordered lesion on the upper lip of a male Japanese patient. The diagnosis is oral melanoma. Courtesy Dr Bob Goode, Tuf....

The palate and maxillary gingiva are involved in approximately 80% of patients, but buccal mucosa, mandibular gingiva, and tongue lesions are also identified. The oral mucosa is primarily involved in less than 1% of melanomas. Metastatic melanoma most frequently affects the mandible, tongue, and buccal mucosa.

Features of long-standing lesions include elevation, color variegation, ulceration, and satellite lesions that may have the appearance of physiologic pigmentation.

A neck mass may be present, indicating regional metastasis; however, this is rare unless the primary tumor is extensive.

References

Staging

Prasad et al^[8]and Patel et al^[9]proposed microstaging for lymph node–negative tumors, as follows:

Level I – Melanoma in situ (noninvasive)
Level II – Invasion of the lamina propria only
Level III – Invasion of deeper tissues (skeletal muscle, bone, or cartilage)

Median survival declines with each increasing level of invasion.

The American Joint Committee on Cancer (AJCC) does not have published guidelines for the staging of oral malignant melanomas. Most practitioners use general clinical stages in the assessment of oral mucosal melanoma, as follows:

Stage I – Localized disease
Stage II – Regional lymph node metastasis
Stage III – Distant metastasis

Lesions thinner than 0.75 mm rarely metastasize, but they do have the potential to do so. On occasion, a small primary lesion is discovered after a symptomatic lymph node is harvested.

References

Differential Diagnosis

Tissue biopsy is the only study that is effective in diagnosing oral malignant melanoma. Perform clinical examination, and biopsy suspicious, unexplained lesions. Diseases and pigmented entities that should be considered when evaluating a patient with suspected oral malignant melanoma include the following:

Addison Disease
Blue Nevi
Ephelides (Freckles)
Dermatological Manifestations of Kaposi Sarcoma
Oral Nevi

Other conditions to be considered include the following:

Amalgam or graphite tattoo
Melanocytoma
Oral melanotic macule
Peutz-Jeghers syndrome
Laugier-Hunziker syndrome
Physiologic pigmentation

Tattoos

The amalgam tattoo, as shown below, is a frequent finding in persons who have had dental amalgam restorations (ie, silver fillings in teeth). When the amalgam is removed with a high-speed dental handpiece, amalgam particles can be embedded or traumatically implanted in the oral mucosa. Silver from the amalgam leeches out of the embedded particles and stains (ie, tattoos) selected components of the fibrous connective tissue (eg, elastic, reticulin, oxytalan fibers) and highlights the blood vessels.

The pigment is often solitary, macular, gray-black, and found near where amalgams were placed and subsequently removed. The gingiva, palate, lateral tongue, and buccal mucosa are commonly involved sites. If the particle is large enough, a dental radiograph may show radiopaque amalgam particles in the soft tissue or bone. Fragments of the amalgam can be observed on histologic specimens, and, on occasion, a foreign body giant cell reaction is noted.

View Image

This image depicts 2 diffusely bordered, dark gray macules in the left posterior buccal mucosa adjacent to molar teeth that have been restored. The di....

Graphite tattoos result from pencil lead that is traumatically implanted, usually during the elementary school years. A gray-black pigmented, often macular area, commonly found in the palate, corresponds to the size of the implanted lead or the rub from its introduction. Older persons with these tattoos may not be able to recall the event.

Lead shot and bullets also leave "rub" tattoos in the soft tissue of people who experience such violence. Heavy metal ingestion, such as with lead, bismuth, or even the chemotherapeutic agent cisplatin, often creates linear pigmentation in areas of inflammation, referred to as Burton lines. Plaque bacteria provide sulfides for metallic salt deposition.

Although "asphalt" tattoos are less common on mucosal surfaces than on cutaneous surfaces, they are a source of pigmentation. These tattoos can occur occur in healed skin after bikers, runners, or the uncoordinated slide across paved surfaces ("road rash").

Intentional tattoos are readily identifiable. They are often words of emotion, vulgarities, letters, or symbols placed by the persons themselves or a tattoo artist. The tattoos are often deeply pigmented with a single color or a variety of colors. In some cases of self-mutilating behavior, the tattoos are blotchy, irregular, and alarming in appearance.

Blood and melanin coloration

Coloration imparted by blood can result from the pooling of red blood cells (RBCs) in vessels (eg, hyperemia, sludging, presence of a thrombus), increased vascularity, or extravasation after an injury. The red, blue, or purple color due to intravascular blood can be blanched during diascopy, in which pressure is placed on the mucosa by using a glass slide or a test tube. This examination can be used to identify telangiectasias, varicosities, and hemangiomas, to an extent. Kaposi sarcoma, which is often observed in the mouths of patients with acquired immunodeficiency syndrome (AIDS), is a red to violaceous, vascular proliferation caused by human herpesvirus (HHV) 8; it does not blanch on diascopy. The discoloration is due to extravasation of blood coupled with vascular proliferation.

Ecchymosis and petechiae, due to bruising and negative pressure, are common in the junctional area of the hard and soft palates. These extravasated blood-related discolorations are noted frequently in mononucleosis, patients who violently cough, those who forcefully “hark and spit,” and those who engage in oro-genital sex.

Melanin pigmentation is a common feature of the oral mucosa. This pigmentation is observed diffusely as racial pigmentation, which can be patchy, and focally as melanotic macules and nevi (see the first image below). The relative constancy of the brown color, without variegation, indicates its benign status. However, melanoacanthoma, which is deeply brown-black, can arise suddenly and grow large. Although melanoacanthoma commonly occurs on the buccal mucosa of black women, it can appear on the palate (see the second image below). The lesion is often suggestive of melanoma; however, it represents a benign, possibly reactive process.

View Image

Clinical photo of an irregularly shaped, tan-brown macule in the right side of the posterior hard palate. The diagnosis is oral melanotic macule.

View Image

Clinical photo of the buccal mucosa of a middle-aged, black woman with a brown-black, irregularly bordered macule that arose suddenly. The patient was....

Melanocytomas and melanocytic macules

Melanocytomas (nevus of Ota), benign hamartomas common in the optic disc and the uveal tract in the pigmented races, are deeply pigmented and, on rare occasion, have undergone malignant transformation. These lesions have been described in cutaneous areas (scalp) and the meninges, and, when in the spinal tract, are said to have a more aggressive course. Mucosal lesions have been described in the veterinary literature. Pigmented epithelioid melanocytoma is a melanocytic neoplasm with a Carney complex (myxomas, mucocutaneous hyperpigmentation, endocrinopathy) association. The lesion is frequently deeply pigmented and occurs on skin and mucosal surfaces. While it can metastasize to lymph nodes, the long-term prognosis is favorable.^[10]

Melanotic macules are common on the lip, but they are also found in the oral cavity. They can be extensive in Peutz-Jeghers syndrome and are perioral or intraoral. In Addisonian pigmentation and pigmentation caused by certain medications, the etiology involves the activity of melanocyte-stimulating hormone (MSH). Bronzing associated with adrenal insufficiency is diffuse and commonly uniform. When the adrenal cortex does not respond to pituitary-released corticotropin, the continued release depletes corticotropin. A precursor protein to corticotropin and MSH is released (pro-opiomelanocortin); this protein causes the increased pigmentation.

Drug-induced coloration

Medication-induced pigmentation may be tan, light and dark brown, or blue-black and appear more localized and blotchy. Estrogen, chemotherapy agents (eg, imatinib, Cis-platinum, doxorubicin^[11]), laxatives, zidovudine or azidothymidine (AZT), antimalarials (eg, hydroxychloroquine [Plaquenil]), and minocycline are frequent culprits. The drugs may stimulate melanin production, may produce postinflammatory hypermelanosis, or may have metabolites that deposit in and pigment the tissues.

References

Radiologic Studies

Imaging studies, such as computed tomography (CT) scanning, may be of benefit in determining the extent of the tumor when contrast enhancement is used. Contrast-enhanced CT can be used to determine the extent of the melanoma and whether local, regional, or lymph node metastasis is present.

Studies such as bone scanning with a gadolinium-based agent and chest radiography can be beneficial in assessing metastasis.

Magnetic resonance imaging (MRI) is used to diagnose melanoma in soft tissue. Atypical intensity is correlated with the amount of intracytoplasmic melanin. On T1-weighted images, such melanomas are hypointense. On T2-weighted images, such melanomas are hyperintense and show increased melanin production. To the author's knowledge, oral melanomas are not assessed in this manner.

Positron emission tomography (PET) has poor results in distinguishing melanoma from nevi. However, combined PET-CT scanning may have diagnostic value and may be used in postsurgical follow-up as a monitor for recurrence.^[12]

Gadolinium warning

Gadolinium-based contrast agents (gadopentetate dimeglumine [Magnevist], gadobenate dimeglumine [MultiHance], gadodiamide [Omniscan], gadoversetamide [OptiMARK], gadoteridol [ProHance]) have been linked to the development of nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy (NFD). For more information, see Nephrogenic Systemic Fibrosis. The disease has occurred in patients with moderate to end-stage renal disease after being given a gadolinium-based contrast agent to enhance MRI or MRA scans.

NSF/NFD is a debilitating and sometimes fatal disease. Characteristics include red or dark patches on the skin; burning, itching, swelling, hardening, and tightening of the skin; yellow spots on the whites of the eyes; joint stiffness with trouble moving or straightening the arms, hands, legs, or feet; pain deep in the hip bones or ribs; and muscle weakness.

References

Biopsy

The only study effective in diagnosing oral malignant melanoma is a tissue biopsy. Perform a thorough clinical examination and a biopsy of suspicious, unexplained lesions. Surgical lymph node harvest depends on the identification of positive nodes at clinical or imaging examination.

The palate and oral cavity are readily accessible for visual inspection. A pigmented lesion in the oral cavity always suggests oral malignant melanoma. Any pigmented lesion of the oral cavity for which no direct cause can be found requires biopsy. In patients with a previous diagnosis of melanoma, close clinical follow-up with a thorough examination is performed at routinely scheduled appointments.

Sentinel-node biopsy or lymphoscintigraphy, which is beneficial in staging of cutaneous melanoma, has less value in staging or treating oral melanoma. Complex and ambiguous drainage patterns may result in the bypass of some first-order nodes and in the occurrence of metastasis in contralateral nodes.

References

Histologic Findings

Although any of the features of cutaneous malignancy can be found, most oral melanomas have characteristics of the acral lentiginous (mucosal lentiginous) and, occasionally, superficial spreading types.

The presence of pigmentation brings the possible diagnosis of melanoma to the fore, but iron stains and melanin bleaching may be necessary to characterize the pigmentation. An absence of pigmentation requires greater emphasis on recognition of cytomorphologic and architectural characteristics of melanoma, as well as recognition of lymphocytes in the inflammatory reaction in an amelanotic melanoma.

The malignant cells often nest or cluster in groups in an organoid fashion; however, single cells predominate at the junction in portions of the epithelium (see the images below). There is little evidence of maturation or dispersion at the base of the tumor.

View Image

Histologic image of a polypoid mass. Rounded collections or nests of melanocytes fill the connective tissue and have tropism for the surface epitheliu....

View Image

Tumor cells show affinity for the surface epithelium (merging of tumor and epithelium). In this image, cellular pleomorphism and smudged nuclei with p....

The melanoma cells have large nuclei, often with prominent eosinophilic nucleoli, and show nuclear pseudoinclusions due to nuclear membrane irregularity (see the following image). The abundant cytoplasm may be uniformly eosinophilic or optically clear. Fine and coarse intracytoplasmic pigment may be evident. Occasionally, the cells become spindled (sarcomatoid) or neurotize in areas. In the oral mucosa, the prognosis is dismal for patients with any architectural type (spindled, pleomorphic, plasmacytoid, undifferentiated) of cell. Metastatic spread to the cervical and supraclavicular lymph nodes is a common finding.

View Image

This image shows rounded nest of various sized melanocytes with nuclear pseudoinclusions (hematoxylin and eosin, original magnification, ×40). The dia....

References

Immunochemistry

Melanomas have a number of histopathologic mimics, including poorly differentiated carcinomas, PEComas (perivascular epithelioid cell tumors), and anaplastic large-cell lymphomas. Balloon cell, small cell, and desmoplastic variants of melanoma may be primary or metastatic in the oral mucosa. Differentiation requires the use of immunohistochemical (IHC) techniques to highlight intermediate filaments or antigens specific for a particular cell line. Proliferative markers such as Ki-67, p53, and bcl-2 are useful in separating benign from malignant melanocytic lesions, with Ki-67 being the most useful.

Amelanotic melanomas can resemble many different mesenchymal neoplasms, and immunohistochemical stains must be used for diagnosis. The astute pathologist will look for evidence of a lymphocytic reaction within the connective tissue and an increased number of melanocytes in the basal cell layer as an indication to request immunohistochemical staining.

Leukocyte common antigen and Ki-1 are used to identify the lymphocytic lesions. Cytokeratin markers, often cocktails of high– and low–molecular-weight cytokeratins, can be used to help in the identification of epithelial malignancies.

S-100 protein and homatropine methylbromide (HMB-45) antigen positivity are characteristic of, although not specific for, melanoma. S-100 protein is frequently used to highlight the spindled, more neural-appearing melanocytes, whereas HMB-45 is used to identify the round cells (see the images below). Melanomas, unlike epithelial lesions, are identified by using vimentin, a marker of mesenchymal cells.

View Image

This image depicts tumor cell cytoplasmic homatropine methylbromide (HMB-45) immunohistochemical staining (original magnification, ×40). The diagnosis....

View Image

This polypoid mass with tumor cells shows strong, positive staining with S-100 protein immunohistochemical stain (original magnification, ×2). The dia....

Microphthalmic-associated transcription factor (MITF), tyrosinase, and melanoma antigen recognized by T-cells 1 (MART-1)/Melan-A immunostains have been used to highlight melanocytes. The inclusion of these stains in a panel of stains for melanoma may be beneficial. The use of at least 2 different immunostains is recommended for diagnosis.

MITF has value in decorating amelanotic melanomas and desmoplastic melanomas when other immunohistochemical stains have failed. S-100 protein and tyrosinase show the highest percentage of positivity. MART-1/Melan-A is reported to be much more useful than HMB-45 for highlighting melanocytic tumors, but because it is a marker of melanocyte lineage, benign lesions such as melanocytic nevi also stain.

References

Medical Management

Aggressive surgery remains the treatment of choice. Medical therapy is not often beneficial for treating oral melanoma. Chemotherapeutic medications for the treatment of oral melanoma do not reliably reduce tumor volume. Interferon, dacarbazine, and Bacillus Calmette-Guerin (BCG) vaccine have been tried with marginal and unpredictable results. Protocols with interferon (IFN) (Intron A) and other immunotherapies are common.

Multimodal therapy offers the best likelihood of relapse-free survival compared with any single therapy. Kirkwood et al^[13] showed that surgery followed by high-dose IFN-alfa-2b in high-risk, cutaneous melanoma appears to be more beneficial than surgery followed by melanoma antigen vaccination. Although not evaluated in mucosal sites, these approaches may provide valuable adjuncts to the treatment of oral mucosal melanoma. Note that INF-A use is associated with malaise, flulike symptoms, fever, and myalgia.

Drug, radiation, immunologic therapy

Drug therapy (dacarbazine), therapeutic radiation, and immunotherapy are used in the treatment of cutaneous melanoma, but they are of questionable benefit to patients with oral melanoma. Dacarbazine is not effective in the treatment of oral melanoma; however, dacarbazine administration in conjunction with interleukin 2 (IL-2) may have therapeutic value. Ipilimumab, a human monoclonal antibody, has shown encouraging results in therapy for metastatic melanoma.^[14]The drug blocks regulation of cytotoxic T-lymphocytes and allows sustained immunologic activity against melanoma and other malignancies. Metastatic melanomas with either amplification of C-KIT-a transmembrane tyrosine kinase, or BRAF oncogene mutation have shown tumor volume reduction with targeted immunotherapy. Vemurafenib and dabrafenib have been effective in treating melanoma with a BRAF mutation.^[15]Imatinib and other inhibitors of C-KIT have resulted in either partial or complete responses in patients harboring C-KIT mutations.^[16]Current studies are evaluating many other tyrosine kinase inhibitors in the class of imatinib.^[17]

Experience with oral malignant melanoma is largely derived from single cases. Anecdotal reports describe success with IFN-alfa or hyperfractionated radiation therapy. Many cancer centers follow surgical excision with a course of IL-2 as adjunctive therapy to prevent or limit recurrence. Peginterferon alfa-2b (Sylatron) has been approved by the US Food and Drug Administration (FDA) for melanoma with microscopic or gross nodal involvement within 84 days of definitive surgical resection including complete lymphadenectomy.

Because of the rarity of the lesions, assembling a cohort study group to evaluate the different therapeutic regimens is difficult. The hope is that future research will incorporate standardized multimodal therapy, such as those used in the treatment of cutaneous melanoma.

References

Surgical Management

As primary therapy, ablative surgery with tumor-free margins remains the treatment of choice unless lymph node or distant metastasis exists. Early surgical intervention when local recurrence is detected enhances survival, because the dismal outcomes are associated with distant metastasis. About 80% of patients with oral melanoma have local disease, and 5-10% of patients present with grossly involved cervical and/or supraclavicular lymph nodes. After complete surgical excision, the local-regional relapse rate is reported to be 10-20%, and 5-year survival rates are clustered around 10-25%, with a reported range of 4.5-48%. McKinnon et al reported that tertiary care centers have the best results.^[18]

Electrodesiccation and cryosurgery are described as treatment modalities for early, superficial, palatal lesions. However, incomplete removal results in recurrence that may envelop the previous biopsy, excision, or treatment site and interfere with histologic evaluation. These methods have little or questionable benefit in the treatment of oral melanoma.

Although radiation alone is reported to have questionable benefit (particularly in small fractionated doses), this therapy is a valuable adjuvant in achieving relapse-free survival when high-fractionated doses are used.^[19] Radioimmunotherapy trials are currently under way at many large medical centers.

Surgical lymph node harvesting depends on the identification of positive nodes at clinical or imaging examination. Neither lymphoscintigraphy nor intraoperative blue-dye sentinel-node biopsy (eg, selective neck dissection) is useful in predicting drainage patterns in oral melanomas. Anatomic ambiguity appears to preclude consistent assessment of oral lymphatic drainage patterns when this technique is attempted.

Prophylactic neck dissection (ie, elective neck dissection) is not advocated as a treatment for oral melanoma.

Eventually, multimodal therapy may be proven effective in the treatment of oral mucosal melanoma.

References

Consultations

Consult the following specialists and facilitate their meeting during head and neck tumor boards to plan the best therapy and aftercare for patients with oral melanoma:

Ear, nose, and throat (ENT) surgeon
Pathologist (eg, dermatopathologist and general surgical, head and neck, or oral and maxillofacial specialist)
Medical and radiation oncologists
Maxillofacial prosthodontists
Speech therapist
Nutrition counselor

The primary concern is ensured surgical removal; secondary concerns deal with restoring function and cosmetic results. If the anatomy restricts ensured removal, medical oncologists and radiation oncologists must provide the most appropriate adjunctive therapy.

Maxillofacial prosthodontists can provide advice about the appliances available and about tissue requirements for support and retention. In addition, surgery mostly likely results in compromised oral function, which affects speech and nourishment. Rehabilitation and constant reinforcement may be important in restoring function.

Nutritional counseling is helpful. Loss of teeth and significant bony anatomy make eating difficult. Depending on the extent of surgery, dietary modifications may be necessary until obturators and dental appliances are fabricated and placed to restore function. Chewing and deglutition may be severely compromised, and aspiration may be possible. Retraining may be necessary to facilitate swallowing and to protect the swallowing reflex. Patients may have difficulty eating and gravitate toward soft diets. However, soft diets are cariogenic and often high in fat and calories.

The involved consultants should be aware of the recall schedule to assess patient progress and adaptation.

References

Lifelong Follow-Up

Diagnosis and subsequent surgical excision of oral melanoma requires lifelong follow-up. Periodic follow-up for oral examination and assessment is necessary to evaluate for recurrence. Healthcare practitioners, including physicians, nurses, and dental personnel must encourage the patient to adopt healthy behaviors. For the life of the patient, healthcare providers must regularly perform thorough oral examinations and imaging studies to rule out recurrence and to recognize and treat oral disease. Recurrence has been described as long as 11 years after the initial surgery. Early discussions of potential problems with function, prostheses, oral fungal infection, and lesion recurrence may ensure patient compliance. At follow-up visits, dental care, nutritional status, and difficulties with the prosthesis (if necessary) can be addressed. In addition, patient comfort and function can be assessed, and the treatment or the follow-up schedule can be modified.

References

Prevention

Although preventive strategies for cutaneous melanoma are well known, no such strategies for oral malignant melanoma are known. Encourage patients to perform a thorough oral self-examination and to report any abnormal findings to their dentist or physician. Oral lesions that are pigmented, bleed, and have mass should be evaluated early.

Teach the patient how to perform an effective oral examination. All oral mucosal surfaces available for inspection should be visualized. This examination requires a bit of dexterity and head movement to reflect light appropriately. Adequate oral examination requires good lighting, a mouth mirror, and a 2 X 2-inch gauze sponge (and a bathroom mirror for self-inspection). The tongue is retracted and moved from side to side with the 2 X 2-inch gauze to achieve an unobstructed view.

The most significant findings with self-examination are pigmentary changes; however, masses, ulcers, plaques, and altered sensation are also suggestive of malignant melanoma.

Healthcare practitioners can reinforce this practice at follow-up appointments and ask patients to demonstrate their skill.

References

Prognosis

As expected, the best prognosis is achieved with early recognition and complete excision, before significant invasion and metastasis have occurred. Oral melanoma is often overlooked or clinically misinterpreted as a benign pigmented process until it is well advanced. Radial and vertical extension is common at the time of diagnosis. The anatomic complexity and lymphatic drainage of the region dictate the need for aggressive surgical procedures.

The relative rarity of mucosal melanomas has dictated that tumor staging be based on the broader experience with cutaneous melanoma. Oral melanomas seem uniformly more aggressive and spread and metastasize more rapidly than other oral cancers or cutaneous melanomas. Early recognition, diagnosis, and treatment, that being assured surgical removal, greatly improves the prognosis.

In a large study (1074 mucosal melanomas), when the lymph node status was known, 30% of patients with mucosal melanomas had positive nodes. When lymph node metastasis occurs, the prognosis worsens precipitously. For example, the 5-year survival rate in patients with positive nodes is 16.4% as opposed to 38.7% in patients with negative nodes.

The prognosis for patients with oral malignant melanoma is poor, with the 5-year survival rate at 10-25%. Early recognition and treatment (surgical ablation) greatly improves the prognosis. As a result of the absence of corresponding histologic landmarks in the oral mucosa (ie, papillary and reticular dermis), Clark levels of cutaneous melanoma are not applicable to those of the oral cavity. However, tumor thickness or volume may be a reliable prognostic indicator.

Late discovery and diagnosis often indicate the existence of an extensive tumor with metastasis. After surgical ablation, recurrence and metastasis are frequent events, and most patients die of the disease in 2 years. A review of the literature indicates that the 5-year survival rate within a broad range of 4.5-48%, but a large cluster occurs at 10-25%.

The best option for survival is the prevention of metastasis by surgical excision of any recurrent tumor. Eneroth and Lundberg stated that patients are not cured of oral melanoma and that the risk of death always exists.^[20]Long periods of remission may be punctuated by sudden and silent recurrence.

References

Special Considerations

Misdiagnosis and the failure to diagnose are most commonly associated with nonpigmented oral malignant melanomas. Clinically, a lesion may be mistaken for a benign pigmented lesion, a reactive process, or an anatomic variation. This mistake can be made especially when the examination is cursory or performed by healthcare providers who are unfamiliar with oral examination. The best advice is to perform a systematic and thorough examination.

Histologically, amelanotic melanomas require the use of special stains because of the pathologic mimics. Appropriate immunohistochemical stains or panels can be used to distinguish possible considerations such as lymphoid, epithelial, and neuroendocrine lesions.

Pregnant patients

Historically, oral malignant melanoma was reported to progress more rapidly in pregnant females for unknown reasons. This finding was refuted by Borden,^[21]who reiterated that the only reliable prognostic indicator is the stage of the disease at diagnosis and not pregnancy. Although medical therapy and radiation therapy are necessarily curtailed during pregnancy; these treatments usually are not an issue in patients with oral malignant melanoma. However, surgery during pregnancy is problematic because of the requirements for anesthesia and analgesics.

The consideration of pregnancy termination or therapeutic abortion is not clearly justified. The decision must rest with the parents, obstetrician-gynecologist, and surgeon responsible for treating the malignancy.

References

Author

Bobby McManus Collins, II, DDS, MS, Clinical Associate Professor of Oral and Maxillofacial Pathology, Division Director, Oral and Maxillofacial Pathology, Department of Surgical Sciences, East Carolina University School of Dental Medicine