Pigmented Lesions of Oral Mucosa

Introduction

Healthy oral soft tissues typically present a pink to red hue with slight topographical variations in color.
This coloration arises from the interaction of several factors:
- Presence or absence of keratin on the surface epithelium.
- Quantity and location (superficial or deep) of blood vessels in the stroma.
- Presence of adipocytes.
- Absence of melanin pigmentation in the basal cell layer.

Melanin and Exogenous Pigmentation

Melanin, synthesized by melanocytes and nevus cells, can appear brown, blue, or black depending on:
- The amount of melanin present.
- Its spatial location within the tissue (superficial vs. deep).
Exogenous pigmentations are usually associated with:
- Traumatic events.
- Iatrogenic events, resulting in the deposition of foreign material into mucosal tissues.
In some cases, substances may be:
- Ingested, absorbed, and distributed hematogenously into connective tissues.
- Particularly in areas subject to chronic inflammation, such as the gingiva.
Ingested substances can also stimulate melanin production, precipitating color change.
Chromogenic bacteria can produce oral pigmentation, usually discoloring the dorsal tongue.
Certain foods, drinks, and confectionaries can cause exogenous pigmentation. However, discoloration is usually easily reversed.

Endogenous Pigmentation

Melanin is a pigment derived from tyrosine and is synthesized by melanocytes.
Melanocytes reside in the basal cell layer of the epithelium.
Melanin protects against the damaging effects of actinic irradiation.
Melanocytes act as scavengers against various cytotoxic intermediates.
Melanosis describes diffuse hyperpigmentation.

Overproduction of Melanin

Overproduction of melanin may be caused by:
- Increased sun exposure (most common).
- Intraorally, hyperpigmentation is more commonly due to:
  - Physiologic or idiopathic sources.
  - Neoplasia.
  - Medication or oral contraceptive use.
  - High serum concentrations of pituitary adrenocorticotropic hormone (ACTH).
  - Post-inflammatory changes.
  - Genetic or autoimmune disease.
If the etiology of pigmentation cannot be clinically ascertained, a tissue biopsy is warranted to rule out malignant melanoma, which can present with a benign clinical appearance.

Freckle/Ephelis

The cutaneous freckle, or ephelis, is a common, asymptomatic, small (1-3 mm), well-circumscribed, tan- or brown-colored macule.
Often seen on sun-exposed regions of the facial and perioral skin.
Most commonly observed in light-skinned individuals, especially red- or light blond-haired individuals.
Thought to be developmental in origin.
More abundant and darker during childhood and adolescence.
Darker during periods of prolonged sun exposure (spring, summer) and less intense during autumn and winter.
Increase in pigmentation is solely related to an increase in melanin production without increased melanocyte number.
The number of ephelides and color intensity diminish with increasing age.
Generally, no therapeutic intervention is required.

Oral/Labial Melanotic Macule

A unique, benign, pigmented lesion.
Trauma has been postulated to play a role; sun exposure is not a precipitating factor.
Develops more frequently in females, usually on the lower lip (labial melanotic macule) and gingiva.
May develop at any age but generally presents in adulthood.
Congenital melanotic macules have also been described, primarily on the tongue.
Small (<1 cm), well-circumscribed, oval or irregular in outline, and often uniformly pigmented.
Unlike an ephelis, a melanotic macule does not darken with continued sun exposure.

Oral Melanoacanthoma

Benign, reactive melanocytic lesion unique to mucosal tissues.
Acute trauma or chronic irritation usually precedes its development.
May spontaneously resolve.
More common in females in their 3rd to 4th decade; 50% occur in the buccal mucosa.

Melanotic Nevi

Arise as a consequence of melanocytic growth and proliferation.
Genetic and environmental factors, including sun exposure, play a role.
Can be acquired or congenital (associated with Turner’s syndrome).
More common cutaneously in males and mucosally in females.
Common locations include the hard palate and gingiva.
Usually located in the basal layer.

Blue Nevus

The “common” blue nevus is the most frequent histologic variant seen in the oral cavity.
Characterized by an intramucosal proliferation of pigment-laden, spindle-shaped melanocytes.
Appears blue because melanocytes reside deep in the connective tissue, and overlying blood vessels dampen the brown coloration of melanin.
Biopsy is indicated, and surgery is the treatment of choice.

Malignant Melanoma

The least common but most deadly of all primary skin cancers.
Risk factors include:
- Sun exposure, especially at a young age.
- Immunosuppression.
- Multiple cutaneous nevi.
- Family history of melanoma.
More common in light-skinned individuals but higher mortality in dark-skinned individuals.
More common in males over 45 years of age.
The palate is the most commonly involved intraoral site.

Clinical Appearance of Oral Melanomas

Oral melanomas have no distinctive clinical appearance.
They may be macular, plaque-like, or mass-forming, well-circumscribed or irregular.
They exhibit focal or diffuse areas of brown, blue, or black pigmentation.
Up to one-third of oral melanomas may exhibit little or no clinical evidence of pigmentation (amelanosis).
May present with multifocal areas of pigmentation due to tumors exhibiting both melanotic and amelanotic areas.

ABCDE Criteria for Cutaneous Melanoma

Clinical characteristics of cutaneous melanoma are best described by the ABCDE criteria:
- Asymmetry.
- Irregular Borders.
- Color variegation.
- Diameter greater than 6 mm.
- Evolution or surface elevation.
These criteria are useful in differentiating cutaneous melanoma from other focally pigmented melanocytic lesions.
Four main clinicopathologic subtypes of melanoma:
- Superficial spreading melanoma.
- Lentigo maligna melanoma.
- Acral lentiginous melanoma.
- Nodular melanoma.

Multifocal/Diffuse Pigmentation: Physiologic Pigmentation

Dark-skinned individuals (Blacks, Asians, and Latinos) frequently show patchy to generalized hyperpigmentation of oral mucosal tissues.
In many patients, the pigment is restricted to the gingiva.
The pigment is typically first observed during childhood and does not develop de novo in adults.
Sudden or gradual onset of diffuse mucosal pigmentation in adulthood, even in darker-skinned patients, should alert the clinician to consider a pathological condition.

Medication-Induced Pigmentation

Antimalarials, including chloroquine, hydroxychloroquine, and quinacrine, are often used for the treatment of autoimmune diseases.
Other common classes of medications that induce melanosis include:
- Phenothiazines (e.g., chlorpromazine).
- Oral contraceptives.
- Cytotoxic medications (e.g., cyclophosphamide).
Pigmentation can be localized or diffused.

Smoker’s Melanosis

Diffuse melanosis of the anterior vestibular maxillary and mandibular gingivae, buccal mucosa, lateral tongue, palate, and floor of the mouth is occasionally seen among cigarette smokers.
Melanin synthesis may be stimulated by tobacco smoke products.
Chemical compounds within cigarettes, rather than the actual tobacco, may be causative.
The heat of the smoke may also stimulate pigmentation.

Alcohol and Oral Pigmentation

Alcohol has also been associated with increased oral pigmentation.
In alcoholics, the posterior regions of the mouth, including the soft palate, tend to be more frequently pigmented.
Alcoholic melanosis may be associated with a higher risk of cancers of the upper aerodigestive tract.

Post-Inflammatory Hyperpigmentation

More common in dark-skinned individuals after injury or inflammation; commonly seen on acne-prone faces.
Unusual in the oral cavity but may occur with malignancy, lichen planus, or grafts and surgery.

Melasma

Acquired symmetric melanosis that typically develops on sun-exposed areas of the skin, frequently on the face.
The forehead, cheeks, upper lips, and chin are the most commonly affected areas.
There is a distinct female predilection, and most cases arise in darker-skinned individuals.
Evolves rapidly over a period of a few weeks.
Associated with sun exposure, pregnancy, and contraceptive hormones.

Melanosis Associated with Systemic or Genetic Disease

Addison’s Disease

ACTH also has stimulatory effects on melanocytes.
The first sign of disease may be mucocutaneous hyperpigmentation.
Generalized bronzing of the skin and diffuse but patchy melanosis of the oral mucosa.

Cushing’s Syndrome

Diffuse mucocutaneous pigmentation may be seen.
The pattern of oral pigmentation is essentially identical to that seen in patients with adrenal insufficiency.

Peutz-Jeghers Syndrome

An autosomal dominant disease.
Clinical manifestations include intestinal polyposis, cancer susceptibility, and multiple, small, pigmented macules of the lips, perioral skin, hands, and feet.
The macules may resemble ephelides, usually measuring <0.5 cm in diameter.
The intensity of the macular pigment is not influenced by sun exposure.
Similar-appearing lesions may also develop on the anterior tongue and buccal and labial mucosae.
The lip and perioral pigmentation are highly distinctive, although not pathognomonic for this disease.

Cafe au Lait Pigmentation

May be identified in a number of different genetic diseases, including neurofibromatosis type I, McCune-Albright syndrome, and Noonan’s syndrome.
Cafe au lait spots typically present as tan- or brown-colored, irregularly shaped macules of variable size.

Vitamin B12 (Cobalamin) Deficiency

May be associated with a variety of systemic manifestations, including megaloblastic anemia, various neurologic signs and symptoms, and various cutaneous and oral manifestations, including a generalized burning sensation, erythema, and atrophy of the mucosal tissue.
Diffuse mucocutaneous hyperpigmentation is a rare and poorly recognized complication.
This hyperpigmentation is suggestive of Addison’s disease.
The pigmentation resolves following restoration of vitamin B12 levels.

HIV/AIDS

A significant correlation exists between mucocutaneous pigment and CD4 counts cells/\muLf200.
Immune dysregulation associated with HIV/AIDS leads to increased secretion of \alpha-MSH from the anterior pituitary gland, which may also stimulate increased melanin synthesis.
Patients may present with a history of progressive hyperpigmentation of the skin, nails, and mucous membranes.
The pigmentation resembles most of the other forms of diffuse melanosis.
The buccal mucosa is the most frequently affected site, but the gingiva, palate, and tongue may also be involved.

Hemoglobin and Iron-Associated Pigmentation

Ecchymoses of the oral mucosa may be encountered in patients with liver cirrhosis, leukemia, and end-stage renal disease undergoing dialysis treatment.
Purpura/petechiae may develop as a consequence of trauma, viral, or systemic disease.
In most cases, the petechiae are identified on the soft palate and should resolve within two weeks.
Failure to resolve should arouse suspicion of a hemorrhagic diathesis, a persistent infectious disease, or other systemic disease, and appropriate laboratory investigations must be undertaken.

Hemochromatosis

A chronic, progressive disease characterized by excessive iron deposition (usually in the form of hemosiderin) in the liver and other organs and tissues.
Cutaneous pigmentation is seen in over 90% of affected patients, regardless of the etiology of the disease.
The primary oral manifestation is a blue-gray to brown pigmentation affecting mainly the palate and gingiva.
Complications may include liver cirrhosis, diabetes, anemia, heart failure, hypertension, and bronzing of the skin.

Exogenous Pigmentation

Amalgam Tattoo

Iatrogenic in origin and typically a consequence of the inadvertent deposition of amalgam restorative material into the submucosal tissue.
May be found in up to 1%-3% of the general population.
The lesions are typically small, asymptomatic, macular, and bluish-gray or even black in appearance.
They may be found on any mucosal surface, including:
- Gingiva.
- Alveolar mucosa.
- Buccal mucosa.
- Floor of the mouth near teeth with large amalgam restorations or crowned teeth with amalgams.
- Around the apical region of endodontically treated teeth with retrograde restorations or obturated with silver points.
- In and around healed extraction sites.

Graphite Tattoos

An unusual source of focal exogenous pigmentation.
Most commonly seen on the palate and gingiva and represent traumatic implantation of graphite particles from a pencil.
The lesions may be indistinguishable from amalgam tattoos, often presenting as a solitary gray or black macule.
Since the traumatic event often occurs in childhood, many patients may not report a history of injury.

Medicinal Metal-Induced Pigmentation

Gold and colloidal silver have both been associated with diffuse cutaneous pigmentation.
Silver may cause a generalized blue-gray discoloration (argyria), whereas gold-induced pigment may appear blue-gray or purple (chrysiasis).
Lichenoid eruptions have been associated with systemic gold therapy.
Silver nitrate and zinc oxide can cause focal mucocutaneous pigmentation.
- Silver nitrate cautery has been used to treat recurrent aphthous stomatitis.
- Zinc oxide is a common component of sunblock creams.

Heavy Metal Pigmentation

An occupational and health hazard for some individuals who work in certain industrial plants.
Lead, mercury, bismuth, and arsenic have all been shown to be deposited in oral tissue if ingested in sufficient quantities or over an extended period of time.
These ingested metal salts tend to extravasate from vessels in areas of chronic inflammation.
In the oral cavity, the pigmentation is usually found along the free marginal gingiva, where it often dramatically outlines the gingival cuff.
This metallic line usually has a gray to black appearance.
In some patients, the oral pigmentation may be the first sign of heavy metal toxicity.
Additional systemic signs and symptoms of heavy metal poisoning may include behavioral changes, neurologic disorders, intestinal pain, and sialorrhea.

Drug-Induced Pigmentation

Minocycline, a tetracycline derivative frequently used in the treatment of acne, is a relatively common cause of drug-induced non-melanin-associated oral pigmentation.
Similar to tetracycline, minocycline can cause pigmentation of developing teeth.
Minocycline can also induce actual pigmentation of the oral soft tissues, as well as the skin and nails.
Minocycline-induced soft tissue pigmentation may appear gray, brown, or black and is often patchy or diffuse.
Most patients are prescribed minocycline in early adulthood.
When taken chronically, minocycline metabolites may become incorporated into the normal bone.
The surrounding bone may appear green, blue, or even black, and the palatal and alveolar mucosae may appear similarly and diffusely discolored.
Roots may show a green color, whereas developing roots tend to be black.

Treatment Options for Pigmented Lesions

Focally pigmented lesions warrant removal for both diagnostic and therapeutic purposes.
Apart from cases associated with neoplasia, surgical intervention is less of an option for the treatment of multifocal or diffuse pigmentation.
Drug-induced melanosis and other examples of exogenously stimulated generalized pigmentation may spontaneously subside after withdrawal of the offending substance.
Different thickness flap, gingivectomy, cryotherapy, electrosurgery, bur abrasion, and scraping with a scalpel have been successfully used to treat gingival pigmentation.
Laser therapy has also proven to be an effective modality for use in the treatment of bothersome oral pigmentation; however, the beneficial effects may only be temporary, with recurrence of at least partial pigmentation in upward of 20% of treated patients.
Bleaching creams can also be used.
- A combination of 4% hydroquinone (0.05%) retinoic acid (0.01%) fluocinolone acetonide has proven effective in greater than 90% of patients.
Exogenous ochronosis:
- A form of intense cutaneous hyperpigmentation with or without atrophic striae and coarsening of the skin or formation of numerous coalesced, black papules.
- More commonly observed in black individuals, usually female, who have undergone long-term bleaching therapy.
- The intense color changes develop in the areas where the cream was applied (frequently on the face) and are related to the accumulation of a yellow-brown pigmented substance (not melanin) in the dermis.
- This pigmentation may be permanent.
- Q-switched Nd: YAG laser therapy appears to be effective in reducing the dyschromia associated with exogenous ochronosis.
Several substances, including novel tyrosinase inhibitors, have demonstrable skin-lightening effects in animal models but remain largely experimental and have not yet been proven to be effective in humans.

Depigmentation (Vitiligo)

Hypomelanosis, autoimmunity, cytotoxicity, genetics, and alterations from metabolic or oxidative stress.
Topical corticosteroids, topical calcineurin inhibitors, ultraviolet B narrow band, and psoralen and ultraviolet A exposure have proven to be effective nonsurgical therapies.