Oral Nevi

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Background

In 1943, Field and Ackermann described the features characteristic of intraoral nevi.[1] Oral melanocytic nevi are benign proliferations of nevus cells in the epithelial layer, the submucosal layer, or both. As such, they are classified as junctional, intramucosal, and compound nevi. Nevi may also be classified as congenital or acquired. Unlike their cutaneous counterparts, oral melanocytic nevi are rare.

Intramucosal nevi are typically light brown and dome-shaped. These are the most common type, accounting for 64% of all reported oral nevi.[2] Note the image below.


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Intramucosal nevus on the lower lip. This brown papule measured 0.6 cm in diameter and was only slightly raised. Melanotic macules are invariably flat....

The common blue nevus is the second most common type found in the oral cavity, accounting for 16.5-36% of all oral nevi.[3] Note the image below.


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Blue nevus on the gingiva. This 1-cm saucer-shaped tan macule on the gingiva has histologic features consistent with those of a blue nevus, which is t....

Junctional and compound nevi are uncommon, accounting for only 3-6% and 5.9-16.5%, respectively.[2, 4, 5]

Rarer types include Spitz nevi, cellular blue nevi, congenital nevi, combined nevi, balloon cell nevi, epithelioid blue nevi, plaque-type blue nevi, halo nevi, and neurotized nevi.[6, 7, 8, 9, 10, 11, 12, 13, 14] [15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26] Dysplastic nevi have not been reported in the oral mucosa.

Pathophysiology

Nevus cells are derived from the neural crest. These cells migrate to the skin and oral mucous membranes during embryogenesis. Nevus cell formation probably begins with the proliferation of melanocytes along the basal cell layer and is possibly associated with elongation of the rete ridges. Nevus cells either lack contact inhibition or lose it shortly after the proliferation process begins. They retain melanin pigment and form nests or thèques.

Nevus cells have the ability to migrate from the basal cell layer into the underlying submucosa. Eventually, they may separate from the epidermis. Junctional nests may be lost later, and nevus cells may be confined to the submucosa. As the nevus cells penetrate into the submucosa, their pigmentation diminishes.

Genetic analysis has revealed V600E point BRAF mutation in both oral benign and malignant melanocytic lesions.[27]

Epidemiology

Frequency

United States

The incidence is 0.1-1.15% in the United States.[28, 29] Lesions may be underreported because they often go undetected.

Mortality/Morbidity

No case of melanoma arising in or around an oral melanocytic nevus has been described.

Race

Oral nevi may occur in persons of all races. They are reported more frequently in white patients (55%) than in black patients (23%).[28] The apparent predominance of oral nevi in whites over Asians (14%) and Hispanics (7%) may be due to the over-representation of this group among patients who underwent biopsies.

Sex

Oral mucosal nevi have a slight female predominance (1.5:1 female-to-male ratio), except for the blue nevi type, which occurs equally in both sexes.[4]

Age

The average age at diagnosis is 35 years (range, 3-85 y).[4] Male patients tend to be a few years older than female patients. Patients with junctional and compound nevi are relatively younger, with an average age at diagnosis of 22 and 24 years, respectively.

History

Most oral nevi are solitary and asymptomatic. Congenital melanocytic nevi are present at birth or appear shortly after. Acquired melanocytic nevi begin to appear in early childhood. The lesions are usually detected as an incidental finding on routine dental examination.

Of patients with recorded complaints, 22% described a mass, growth, or pigmented spot.[30] A minority of patients complained of soreness or pain related to another cause, such as an ill-fitting denture. Less than 1 in 10 patients were aware of evolving lesions. Most patients could only speculate about the duration of their condition.

Physical

Benign oral nevi present as asymptomatic, well circumscribed, round or oval macules or papules with smooth surface that range in color from light brown to black.[31] These lesions may rarely present as epulislike swelling of the gingiva and as a hamartoma on the palate, composed of nevus cells, hyperplastic salivary gland tissue, adipose tissue, nerves, and vessels.[32, 33] Oral nevi usually occur as solitary lesions; however, one case of multiple intraoral nevi has been described in the literature.[34] Intramucosal nevi and rarely Spitz nevi may be nonpigmented or amelanotic 15-22% of the time and present as sessile growths that resemble fibromas or papillomas.[7, 30, 33]

The average size of an oral nevus is 0.3-0.5 cm at the largest diameter.[28, 29] Blue nevi are smaller than intramucosal nevi. Larger nevi (>6 mm) are more likely to be congenital.

Intraoral melanocytic nevi most commonly occur on the hard palate, followed by the buccal mucosa. Rarely, the tongue, floor of the mouth,[6, 35] and pharynx may be involved.[21] The distribution varies depending on the histologic type of the nevus. The hard palate is the most common location for blue nevi.[3, 36] The hard palate, buccal mucosa, gingiva, and lips are common locations for intramucosal nevi.[30] See the images below.


View Image

Intramucosal nevus on the lower lip. This brown papule measured 0.6 cm in diameter and was only slightly raised. Melanotic macules are invariably flat....


View Image

Blue nevus on the gingiva. This 1-cm saucer-shaped tan macule on the gingiva has histologic features consistent with those of a blue nevus, which is t....

Oral nevi may be mistaken for other pigmented lesions in the oral cavity secondary to endogenous and exogenous causes. Certain clinical features can assist clinicians in making the correct diagnosis.[37, 38] Melanotic macules and amalgam tattoos are usually flat and 80% of nevi are elevated. Ethnic pigmentation is nearly always symmetric and rarely affects the surface topography or disturbs the normal stippling in the gingiva. Smoker's melanosis involves only the anterior gingiva, and, of course, a history of smoking is essential. Vascular lesions usually blanch with compression and melanocytic proliferations do not. Malignant melanoma is frequently associated with diffuse areas of pigmentation, possible ulceration, nodularity, variegation in color, and an irregular outline.

Causes

See Pathophysiology.

Laboratory Studies

The same tests for cutaneous nevi are available for the assessment of mucosal lesions if concern exists after histologic analysis.

Imaging Studies

Imaging studies typically are not indicated. Periapical radiography may be helpful in differentiating an amalgam tattoo from a nevus by demonstrating minute opaque particles. Angiography may be performed to exclude vascular anomalies.

Other Tests

Aspiration may be performed to differentiate vascular lesions from melanocytic lesions.

Procedures

Biopsy and histologic examination of all pigmented and nonpigmented oral lesions are indicated to confirm the nature of the lesion. The primary diagnostic procedure is excisional biopsy. Incisional biopsy may be performed in lesions larger than 1-2 cm. The incision should be made in the nodular areas, if they exist, and the incisions should start from the center, not from the periphery of the lesion. See the image below.


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This biopsy-proven intramucosal nevus on the gingiva is unusual because it is not raised and has an irregular outline.

Histologic Findings

Oral melanocytic nevi are classified as junctional, compound, or intramucosal (intra–lamina propria) nevi, similar to their cutaneous counterparts. In junctional nevi, there is proliferation of benign melanocytes along the epithelial basement membrane. In compound nevi, the melanocytes are found both in the basal cell layer and in the superficial lamina propria. In intramucosal nevi, the melanocytes are located in the lamina propria and there is no epithelial component. Oral blue nevi are intramucosal proliferations of dendritic melanocytes containing abundant melanin granules in the lamina propria. Combined oral nevi have histologic features of both melanocytic nevi and blue nevi. Intraoral nevi may rarely present histologically with pseudoepitheliomatous hyperplasia.[40]

Oral nevi may also be classified as congenital or acquired. Congenital nevi penetrate the connective-tissue layer in a diffuse sheetlike pattern and tend to “split” into collagen bundles.[15] Perivascular and periappendageal involvement are likely to be congenital nevi.

Immunohistochemical studies may be performed if warranted. The Melan A, MART-1, and Fontana-Masson silver stains react the same way for oral and cutaneous pigmented lesions. Immunoreactions to S-100 protein, S-100 alpha, and S-100 beta antibodies are detected in benign oral nevi, while oral mucosal melanomas in general do not react with the beta subunit, unlike melanomas in the skin.[41] The round cells and spindle cells of benign and malignant oral lesions express HMB-45 and S-100 antigens differently.[42] S-100 expression is more intense and more frequent than HMB-45 expression in the small round cells of intramucosal nevi. The opposite is true in the round cells of mucosal melanomas, for which HMB-45 staining is greater.

In primary oral melanomas, minichromosome maintenance 2 is a more sensitive proliferation marker than Ki-67 and geminin.[43] The ubiquitin protein Skp2 may be a useful marker to differentiate oral benign and malignant melanocytic lesions.[44] High levels of this protein are expressed only in the latter.

Medical Care

Regular and thorough oral examinations should be performed; the goal is to exclude malignant lesions.

Surgical Care

All melanocytic and amelanocytic lesions in the oral cavity should be viewed with suspicion. Complete excision is suggested to be the most reliable approach to oral melanocytic lesions.[45] Evolving and/or recurrent lesions also necessitate excision and microscopic evaluation.

Consultations

Patients may be referred to an oral medicine and/or oral pathology specialist for questionable clinical/histological diagnosis.

Deterrence/Prevention

Because oral nevi are not related to sun exposure, they are impossible to prevent.

Complications

Minor surgical complications may occur.

Prognosis

Reports mainly based on case reports and case series have shown that the prognosis for oral melanocytic nevi is excellent.[46] Only one case of recurrence, in a compound nevus, has been reported.[47] No documented cases of malignant transformation were reported in a cohort of intraoral nevi with up to 2-8 years of follow-up.[21, 48, 46] However, histologic sampling is essential in all oral melanocytic nevi, especially when located in the palate, the most common site of oral melanoma, to exclude and presumably prevent such transformation.

Author

Kara Melissa T Torres, MD, DPDS, Visiting Research Fellow, Ackerman Academy of Dermatopathology

Disclosure: Nothing to disclose.

Coauthor(s)

Dirk M Elston, MD, Director, Ackerman Academy of Dermatopathology, New York

Disclosure: Nothing to disclose.

Specialty Editors

Michelle Pelle, MD, Clinical Assistant Professor, Division of Dermatology, Department of Medicine, University of California, San Diego, School of Medicine

Disclosure: Nothing to disclose.

David F Butler, MD, Section Chief of Dermatology, Central Texas Veterans Healthcare System; Professor of Dermatology, Texas A&M University College of Medicine; Founding Chair, Department of Dermatology, Scott and White Clinic

Disclosure: Nothing to disclose.

Drore Eisen, MD, DDS, Consulting Staff, Department of Dermatology, Dermatology Research Associates of Cincinnati

Disclosure: Nothing to disclose.

Glen H Crawford, MD, Assistant Clinical Professor, Department of Dermatology, University of Pennsylvania School of Medicine; Chief, Division of Dermatology, The Pennsylvania Hospital

Disclosure: Abvie Honoraria Speaking and teaching

Chief Editor

Dirk M Elston, MD, Director, Ackerman Academy of Dermatopathology, New York

Disclosure: Nothing to disclose.

Additional Contributors

Indraneel Bhattacharyya, DDS, MSD Associate Professor, Department of Oral and Maxillofacial Diagnostic Sciences, Director of Oral & Maxillofacial Pathology Residency Program, University of Florida, College of Dentistry

Indraneel Bhattacharyya, DDS, MSD is a member of the following medical societies: American Academy of Oral and Maxillofacial Pathology, American Association for Dental Research, American Dental Association, International Association for Dental Research, and International Association of Oral Pathologists

Disclosure: Nothing to disclose.

Donald Cohen, DMD, MS Professor of Oral and Maxillofacial Pathology, Department of Oral and Maxillofacial Diagnostic Sciences, University of Florida College of Dentistry

Donald Cohen, DMD, MS is a member of the following medical societies: American Academy of Oral and Maxillofacial Pathology

Disclosure: Nothing to disclose.

References

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Intramucosal nevus on the lower lip. This brown papule measured 0.6 cm in diameter and was only slightly raised. Melanotic macules are invariably flat.

Blue nevus on the gingiva. This 1-cm saucer-shaped tan macule on the gingiva has histologic features consistent with those of a blue nevus, which is the second most common type of oral nevus. This location is atypical because most blue nevi occur on the palate.

Intramucosal nevus on the lower lip. This brown papule measured 0.6 cm in diameter and was only slightly raised. Melanotic macules are invariably flat.

Blue nevus on the gingiva. This 1-cm saucer-shaped tan macule on the gingiva has histologic features consistent with those of a blue nevus, which is the second most common type of oral nevus. This location is atypical because most blue nevi occur on the palate.

This biopsy-proven intramucosal nevus on the gingiva is unusual because it is not raised and has an irregular outline.

This biopsy-proven intramucosal nevus on the gingiva is unusual because it is not raised and has an irregular outline.

Intramucosal nevus on the lower lip. This brown papule measured 0.6 cm in diameter and was only slightly raised. Melanotic macules are invariably flat.

Blue nevus on the gingiva. This 1-cm saucer-shaped tan macule on the gingiva has histologic features consistent with those of a blue nevus, which is the second most common type of oral nevus. This location is atypical because most blue nevi occur on the palate.