eMedicine Specialties > Dermatology > Diseases of the Oral Mucosa

Oral Malignant Melanoma: Differential Diagnoses & Workup

Author: Bobby Collins II, DDS, MS, Associate Professor of Oral and Maxillofacial Pathology, Department of Diagnostic Sciences, University of Pittsburgh School of Dental Medicine
Coauthor(s): E Leon Barnes Jr, MD, Professor of Pathology and Professor of Otolaryngology, University of Pittsburgh School of Medicine; John Abernethy, MD, Winston-Salem, North Carolina
Contributor Information and Disclosures

Updated: Mar 21, 2008

Differential Diagnoses

Addison Disease
Blue Nevi
Ephelides (Freckles)
Kaposi Sarcoma
Oral Nevi

Other Problems to Be Considered

Amalgam tattoo
Graphite tattoo
Oral melanotic macule
Peutz-Jeghers syndrome
Physiologic pigmentation

The amalgam tattoo is a frequent finding in persons who have had amalgam restorations (ie, fillings). 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.

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 cisplatin, often creates linear pigmentation in areas of inflammation. 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 after people slide across paved surfaces.

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.

Coloration imparted by blood can result from the pooling of 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 AIDS, is a red-to-violaceous, vascular proliferation caused by human herpesvirus 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 conditions do not blanch with pressure because of blood extravasation. The coloration can vary from blue to red to brown. The greens and yellows associated with hemolysis on the cutaneous surfaces are not commonly observed intraorally.

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. 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. The lesion is often suggestive of melanoma; however, it represents a benign, possibly reactive process.

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.

Medication-induced pigmentation may be more localized and blotchy. Estrogen, chemotherapy agents, zidovudine or azidothymidine (AZT), antimalarials (eg, hydroxychloroquine [Plaquenil]), and minocycline are frequent culprits. The drugs may stimulate melanin production or may have metabolites that pigment the tissues.

Workup

Laboratory Studies

• The only study effective in diagnosing oral malignant melanoma is a tissue biopsy.
• Perform clinical examination and biopsy of suspicious, unexplained lesions.

Imaging Studies

• Imaging studies, such as computed tomography (CT), 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 may have diagnostic value and may be used in postsurgical follow-up as a monitor for recurrence.
• Surgical lymph node harvest depends on the identification of positive nodes at clinical or imaging examination.

Procedures

• The palate and oral cavity are readily accessible for visual inspection.
  • Perform clinical examination and biopsy of suspicious unexplained lesions.
  • In patients with a previous diagnosis of melanoma, clinical follow-up requires a thorough examination.
• 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.
• 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.

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 malignant cells often nest or cluster in groups in an organoid fashion; however, single cells can predominate. The melanoma cells have large nuclei, often with prominent nucleoli, and show nuclear pseudoinclusions due to nuclear membrane irregularity. The abundant cytoplasm may be uniformly eosinophilic or optically clear. Occasionally, the cells become spindled (sarcomatoid) or neurotize in areas. The sarcomatoid architectural finding is interpreted as a more aggressive feature, compared with findings of the round or polygonal cell varieties. In the oral mucosa, the prognosis is dismal for patients with any architectural type (spindled, pleomorphic, undifferentiated) of cell.

Melanomas have a number of histopathologic mimics, including poorly differentiated carcinomas and anaplastic large-cell lymphomas. Differentiation requires the use of immunohistochemical techniques to highlight intermediate filaments or antigens specific for a particular cell line. Amelanotic melanomas can resemble many different mesenchymal neoplasms, and immunohistochemical (IHC) 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 IHC.

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. Melanomas, unlike epithelial lesions, are identified by using vimentin, a marker of mesenchymal cells.
 
Microphthalmic transcription factor, 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. 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.

Staging

Microstaging for lymph node–negative tumors has been proposed by Prasad et al⁴ and Patel et al,⁵ in which level I is melanoma in situ (noninvasive), level II is invasion of the lamina propria only, and level III is invasion of deeper tissues (skeletal muscle, bone, or cartilage). Median survival declines with each increasing level of invasion.

• The American Joint Committee on Cancer 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.

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