Burket, chapter 5

Oral and perioral pigmentation may be physiologic or

pathologic in origin.

However, although an area may appear pigmented, the

discoloration may not be related to actual pigment but

rather to the deposition or accumulation of organic or

inorganic substances, including various metals and drug

metabolites.

Hemoglobin, hemosiderin, and melanin represent the

most common endogenous sources of mucosal color

change.

Pigmented lesions that are of exogenous origin are

usually traumatically deposited directly into the

submucosal tissues.

In some cases, the substances may be ingested,absorbed, and distributed hematogenously, to beprecipitated in connective tissues, particularly inareas subject to chronic inflammation, such asthe gingiva.

In other instances, these ingested substancescan actually stimulate melanin production, thusprecipitating the color change.

Chromogenic bacteria can also produce oralpigmentation, usually resulting in discoloration ofthe dorsal tongue.

Exogenous pigmentation can also be inducedby certain foods, drinks and confectionaries.

Melanin is synthesized within specializedstructures known as melanosomes.

Melanin is actually composed of eumelanin,which is a brown-black pigment, andpheomelanin, which has a red-yellow color.

Melanin pigmentation may be physiologic orpathologic and focal, multifocal, or diffuse in itspresentation.

The term melanosis is frequently used todescribe diffuse hyperpigmentation.

Overproduction of melanin may be caused by avariety of mechanisms, the most common ofwhich is related to increased sun exposure.

However, intraorally hyperpigmentation is more

commonly a consequence of physiologic or

idiopathic sources, neoplasia, medication or oral

contraceptive use, high serum concentrations of

pituitary adrenocorticotropic hormone (ACTH),

postinflammatory changes, and genetic or

autoimmune disease.

In addition to biopsy and histologic study,

various laboratory and clinical tests, including

diascopy, radiography, and blood tests, may be

necessary for definitive diagnosis of oral

pigmentation.

Endogenous Pigmentation Focal Melanocytic Pigmentation:

Freckle/Ephelis:

asymptomatic, small (1–3 mm), well-circumscribed, tan-or brown-colored macule that is often seen on the sun-exposed regions of the facial and perioral skin.

Ephelides are most commonly observed in light-skinnedindividuals and are quite prevalent in red- or light blond–haired individuals.

Ephelides are usually more abundant in number anddarker in intensity during childhood and adolescence.

Freckles tend to become darker during periods ofprolonged sun exposure (spring, summer) and lessintense during the autumn and winter months.

With increasing age, the number of ephelides and colorintensity tends to diminish.

In general, no therapeutic intervention is required.

Oral/Labial Melanotic Macule:

A benign, pigmented lesion that has no known dermal

counterpart.

Melanotic macules are the most common oral lesion of

melanocytic origin.

Sun exposure is not a precipitating factor.

More frequently in females, adulthood, usually in the

lower lip (labial melanotic macule) and gingiva.

Congenital melanotic macules have also been described

occurring primarily in the tongue.

Overall, melanotic macules tend to be small (<1 cm),

well-circumscribed, oval or irregular in outline and often

uniformly pigmented.

Once the lesion reaches a certain size, it does not

tend to enlarge further.

Unlike an ephelis, a melanotic macule does not become

darker with continued sun exposure.

Overall, the oral melanotic macule is a relatively

innocuous lesion, does not represent a melanocytic

proliferation, and does not generally recur following

surgical removal.

DD: melanocytic nevus, malignant melanoma, amalgam

tattoo, and focal ecchymosis.

If such pigmented lesions are present after a 2-week

period, ecchymosis can usually be ruled out, and a biopsy

specimen should be obtained to secure a definitive

diagnosis.

Since oral mucosal malignant melanomas have no

defining clinical characteristics, a biopsy of any persistent

solitary pigmented lesion is always warranted.

Pathology: the basal cells contain an abundance of

melanin pigment without an associated increase in the

number of melanocytes. The pigmentation is often

accentuated at the tips of the rete pegs, and melanin

incontinence into the submucosa is commonly

encountered.

Oral Melanoacanthoma:

Another unusual, benign, melanocytic lesion that isunique to the mucosal tissues.

Oral melanoacanthoma is an innocuous melanocyticlesion that may spontaneously resolve, with or withoutsurgical intervention.

Most patients report a rapid onset; and acute trauma or ahistory of chronic irritation usually precedes thedevelopment of the lesion.

A biopsy is always warranted to confirm the diagnosis,but, once established, no further treatment is required.

Oral melanoacanthoma usually presents as aasymptomatic rapidly enlarging, ill-defined, darklypigmented macular or plaque-like lesion, and mostdevelop in black females.

The majority occur between the third and fourth decadesof life.

In rare instances, multiple lesions may presentsimultaneously.

The buccal mucosa is the most common site ofoccurrence.

Ranging from small and localized to large, diffuse areasof involvement.

The borders are typically irregular in appearance, and thepigmentation may or may not be uniform.

Cutaneous melanoacanthoma represents a pigmentedvariant of seborrheic keratosis and typically occurs inolder Caucasian patients.

Dermatosis papulosa nigra is a relatively common facialcondition that typically manifests in older black patients,often female, and represents multiple pigmentedseborrheic keratoses.

These small papules are often identified in the malar andregions of the face.

proliferation of benign, dendritic melanocytes throughoutthe full thickness of an acanthotic and spongioticepithelial Layer

The biopsy procedure itself may lead to spontaneousregression of the lesion.

Melanocytic Nevus:

Unlike ephelides and melanotic macules, which resultfrom an increase in melanin pigment synthesis, nevi ariseas a consequence of melanocytic growth andproliferation.

In the oral cavity, the intramucosal nevus is mostfrequently observed, followed by the common bluenevus.

Compound nevi are less common, and the junctional

nevus and combined nevus (a nevus composed of two

different cell types) are infrequently identified.

Native melanocytes tend to have a dendritic morphology,

most nevic melanocytes tend to be round, ovoid, or

spindle shaped.

Additional differences include the tendency for nevus cells

to closely approximate one another, if not aggregate in

clusters, and their ability to migrate into and/or within the

submucosal tissues.

The effect of sun exposure on the development of

cutaneous nevi is well recognized. However, there are

also age- and location-dependent differences in the

presentation, number, and distribution of nevi.

Familial atypical multiple mole and melanoma syndrome ischaracterized by the formation of histologically atypicalnevi.

Epithelioid blue nevus may be associated with the Carneycomplex.

Markedly increased numbers of common nevi arecharacteristic in patients with Turner’s syndrome andNoonan’s syndrome and congenital nevi are typicalneurocutaneous melanosis.

The total number of nevi tends to be higher in males thanfemales. In contrast, oral melanocytic nevi are rare,typically present as solitary lesions, and may be morecommon in females.

Oral melanocytic nevi: asymptomatic and often presentas a small (<1 cm), solitary, brown or blue,wellcircumscribed nodule or macule.

Up to 15% of oral nevi may not exhibit any evidence of

clinical pigmentation.

Once the lesion reaches a given size, its growth tends to

cease and may remain static indefinitely.

most are identified in patients over the age of 30.

The hard palate represents the most common site,

followed by the buccal and labial mucosae and gingiva.

Junctional nevi are usually small (<5 mm), macular or

nonpalpable, and tan to brown in appearance.

Over time, the clustered melanocytes are thought to

proliferate down into the connective tissue.

Some nevus cells are still seen at the mucosal

submucosal junction. Such nevi often assume a dome-

shaped appearance and are referred to as compound

nevi.

Intramucosal nevus: the nevus cells completely lose their

association with the epithelial layer and become confined

to the submucosal tissue, often with an associated

decrease in the amount of pigmentation.

The ‘common’ blue nevus, which is the most frequent

histologic variant seen in the oral cavity, is characterized

by an intramucosal proliferation of pigment-laden, spindle-

shaped melanocytes.

The less frequently occurring cellular blue nevus is

characterized by a submucosal proliferation of both

spindle-shaped and larger round or ovoid-shaped

melanocytes.

it is advised that all oral nevi, regardless of histologic type,

be completely removed as they may still represent a

potential precursor of malignant melanoma.

Biopsy is necessary for diagnostic confirmation of an oral

melanocytic nevus since the clinical diagnosis includes a

variety of other focally pigmented lesions, including

malignant melanoma.

Various vascular phenomena may also be considered in

the differential diagnosis. Complete but conservative

surgical excision is the treatment of choice for oral

lesions.

Malignant Melanoma:

The least common but most deadly of all primary skincancers.

A history of multiple episodes of acute sun exposure,especially at a young age; immunosuppression; thepresence of multiple cutaneous nevi; and a family historyof melanoma are all known risk factors for thedevelopment of cutaneous melanoma.

Cutaneous melanoma is most common among whitepopulations that live in the sunbelt regions of the world.

The incidence is increasing in patients, especially males,over the age of 45. In contrast the incidence is decreasingin patients under the age of 40.

Overall, there is a male predilection, but melanoma is oneof the most commonly occurring cancers in women ofchildbearing age.

Melanomas may develop either de novo or, much less

commonly, arise from an existing melanocytic nevus.

On the facial skin, the malar region is a common site for

melanoma since this area is subject to significant solar

exposure.

In general, the clinical characteristics of cutaneous

melanoma are best described by the ABCDE criteria:

asymmetry, irregular borders, color variegation, diameter

greater than 6 mm, and evolution or surface elevation.

There are four main clinicopathologic subtypes of

melanoma.

These include superficial spreading melanoma, lentigo

maligna melanoma, acral lentiginous melanoma, and

nodular melanoma.

In the first three subtypes, the initial growth ischaracterized by radial extension of the tumor cells (radialgrowth phase). In this pattern, the melanocytic tumor cellsspread laterally and therefore superficially.

These lesions have a good prognosis if they are detectedearly and treated before the appearance of nodularlesions, which indicates invasion into the deeperconnective tissue (ie, a vertical growth phase).

The development of nodularity in a previously macularlesion is often an ominous sign.

Tumor thickness (Breslow tumor thickness), the level oftumor involvement in the dermis (Clark’s level of invasion),surface ulceration, vascular or lymphatic invasion,neurotropism, mitotic index, and absence of tumorinfiltrating lymphocytes are all associated with a poorprognosis.

Additionally, various clinical parameters, including tumor

site, age of the patient (>60 years), gender (male), and

regional or distant metastasis, also are predictive of poor

prognosis.

Mucosal melanomas comprise less than 1% of all

melanomas. The majority develop in the head and neck,

most in the sinonasal tract and oral cavity.

The prevalence of oral melanoma appears to be higher

among black-skinned and Japanese people than among

other populations.

The tumor presents more frequently in males than females.

Oral melanoma may develop at any age, but most present

over the age of 50. The palate represents the single most

common site of involvement. The maxillary gingiva is the

second most frequent site.

They may be macular, plaque-like or mass forming, well-

circumscribed or irregular and 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).

Ulceration, pain, tooth mobility or spontaneous exfoliation,

root resorption, bone loss, and paresthesia/anesthesia

may be evident.

DD: melanocytic nevus, oral melanotic macule, and

amalgam tattoo, as well as various vascular lesions and

other soft tissue neoplasms.

It is for this reason a biopsy of any persistent solitary

pigmented lesion is always warranted.

Pathology: The radial or superficial spreading pattern is

often seen in macular lesions; clusters of pleomorphic

melanocytes exhibiting nuclear atypia and

hyperchromatism proliferate within the basal cell region

of the epithelium, and many of the neoplastic cells invade

the overlying epithelium (pagetoid spread) as well as the

superficial submucosa.

Once vertical growth into the connective tissue is

established, the lesions may become clinically

tumefactive.

A history of a previous melanoma, sparing of the palate

and gingiva, amelanosis, and microscopic features, such

as a lack of junctional activity and pagetoid spread, are

findings that may be more suggestive of a metastatic

tumor.

For primary oral melanomas, ablative surgery with wide

margins remains the treatment of choice. Adjuvant radiation

therapy may also be necessary.

Computed tomography and magnetic resonance imaging

studies should be undertaken to explore metastases to the

regional lymph nodes.

Multifocal/Diffuse Pigmentation:

Physiologic Pigmentation:

Physiologic pigmentation is the most common source ofmultifocal or diffuse oral mucosal pigmentation.

Dark-complexioned individuals, including blacks, Asians,South-Americans, frequently show patchy to generalizehyperpigmentation of the oral mucosal tissues.

Although in many patients, the pigment is restricted to thegingiva, melanosis of other mucosal surfaces is notuncommon.

The pigment is often observed in childhood and usually doesnot develop de novo in the adult.

If there is a sudden or gradual onset of diffuse mucosalpigmentation in adulthood, even in darker-skinned patients,other sources for the melanosis should be givenconsideration.

A differential diagnosis may include idiopathic, drug-

induced, or smoking-induced Melanosis.

Hyperpigmentation associated with endocrinopathic and

other systemic disease should also be considered.

Microscopically, physiologic pigmentation is characterized

by increased amounts of melanin pigment within the basal

cell layer.

Etiology of Multifocal, Diffuse, or Generalized Mucocutaneous Melanosis:

Physiologic pigmentation

Laugier-Hunziker pigmentation

Postinflammatory hyperpigmentation

Drug induced

Hormone induced

Adrenal insufficiency

Cushing’s syndrome/Cushing’s disease

Hyperthyroidism

Primary biliary cirrhosis

Hemochromatosis (early stages)

Genetic disease

Vitamin B12 deficiency

HIV/AIDS (late stages)

Malignant melanoma

Drug-Induced Melanosis:

The chief drugs implicated in drug-induced melanosis are

the antimalarials, including chloroquine,

hydroxychloroquine, quinacrine, and others.

Other common classes of medications that induce

melanosis include the phenothiazines, such as

chlorpromazine, oral contraceptives, and cytotoxic

medications such as cyclophosphamide and busulfan.

Intraorally, the pigment can be diffuse yet localized to one

mucosal surface, often the hard palate, or it can be

multifocal and involve multiple surfaces.

Much like other forms of diffuse pigmentation, the lesions

are flat and without evidence of nodularity or swelling.

Sun exposure may exacerbate cutaneous drug-induced

pigmentation.

Medications Associated with Mucocutaneous Pigmentation:

Amiodarone

Amodioquine

Aziodothymidine

Bleomycin

Chloroquine

Chlorpromazine

Clofazamine

Gold

Hydroxychloroquine

Hydroxyurea

Imipramine

Ketoconazole

Mepacrine

Methacycline

Methyldopa

Minocycline

Premarin

Quinacrine

Quinidine

Tacrolimus

Microscopically, there is usually evidence of basilar

hyperpigmentation melanin incontinence without a

concomitant increase in the number of melanocytes.

Hemosiderin and pigmented, yellow or yellow-red, drug

may also be identified.

In most cases, the discoloration tends to fade within a few

months after the drug is discontinued.

Pigmentation associated with hormone therapy may tend

to persist for longer periods of time, despite

discontinuation of the medications.

Smoker’s Melanosis:

Diffuse melanosis of the anterior facial maxillary and

mandibular gingivae, buccal mucosa, lateral tongue,

palate, and floor of the mouth is occasionally seen

among cigarette smokers.

The pigmented areas are brown, flat, and irregular; some

are even geographic or map-like in configuration.

Smokeless tobacco (snuff) does not appear to be

associated with an increase in ora melanosis.

It is possible that one or more of the chemical

compounds incorporated within cigarettes, rather than

the actual tobacco, may be causative. Another possibility

is that the heat of the smoke may stimulate the

pigmentation.

If there is a reduction in smoking, the pigmentation may

eventually resolve.

Histologically, basilar melanosis with melanin incontinence is

observed. Unlike other smoking-related oral pathologies,

smoker’s melanosis is not a preneoplastic condition.

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

than other areas.

It has been suggested that alcoholic melanosis may be

associated with a higher risk of cancers of the upper

aerodigestive tract.

Diffuse or patchy melanotic pigmentation is also

characteristically associated with oral submucous fibrosis.

Unlike smoker’s melanosis, oral submucous fibrosis is a

preneoplastic condition caused by habitual chewing of areca

(betel) nut.

Postinflammatory Hyperpigmentation:

A well-recognized phenomenon that tends to develop

more commonly in dark complexioned individuals. Most

cases present as either focal or diffuse pigmentation in

areas that were subjected to previous injury or

inflammation. The acne-prone face is a relatively common

site for this phenomenon.

Although unusual, postinflammatory pigmentation may

also develop in the oral cavity. In rare cases, the mucosa

overlying a nonmelanocytic malignancy may become

pigmented.

Oral pigmentation has also been described in patients

with lichen planus (lichen planus pigmentosus).

Upon resolution of the lichenoid lesion, the pigmentation

may or may not disappear.

Melasma (Chloasma):

A relatively common, acquired symmetric melanosis that

typically develops on sun-exposed areas of the skin and

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. Unlike other forms of

diffuse melanosis, melasma tends to evolve rather rapidly

over a period of a few weeks. Sun exposure tends to be

an exacerbating, if not precipitating, event.

The term melasma has been used to describe any form of

facial hyperpigmentation, including those related to

postinflammatory changes and medication use.

However, the nomenclature is most appropriately used to

describe the pigmentary changes associated with

pregnancy or ingestion of contraceptive hormones.

Both pregnancy and use of oral contraceptives have also

been associated with oral mucosal melanosis. Rare cases

of idiopathic melasma have also been described in females

and, much less commonly, males. In most cases, it is the

combination of estrogen and progesterone that induces the

pigment.

Estrogen replacement therapy alone, without progesterone,

does not precipitate melasma.

In idiopathic cases, significantly elevated levels of

luteinizing hormone have been identified in both sexes, with

associated decreases in serum estradiol (in women) and

testerone (in males).

Various thyroid abnormalities, including hypothyroidism,

also may play a role in the pathogenesis of pregnancy-

associated melasma.

A biopsy typically reveals basilar melanosis with no

increase in the number of melanocytes. However, the

melanocytes that are present may be larger than those in

the adjacent normally pigmented areas.

Melasma may spontaneously resolve after parturition,

cessation of the exogenous hormones, or regulation of

endogenous sex-hormone levels.

Melanosis Associated with systemic or Genetic Disease:

Hypoadrenocorticism (Adrenal Insufficiency, Addison’s

Disease):

In adults, autoimmune disease represents one of the most

common causes. However, infectious agents, neoplasia, trauma,

certain medications, and iatrogenic causes may lead to adrenal

destruction or an impairment of endogenous steroid production.

In rare cases, adrenal insufficiency may also be a consequence

of genetic disease.

As steroid levels decrease, there is a compensatory activation

of ACTH secretion from the anterior pituitary gland. ACTH then

acts on the adrenal cortex to stimulate steroid production and

ACTH secretion stops. If low steroid level persist, there is a loss

of feedback inhibition, resulting in persistent secretion of ACTH

into the serum. Concurrently the serum levels of a-melanocyte-

stimulating hormone (a-MSH) also increase.

Weakness, poorly defined fatigue, and depression are

some of the typical presenting signs of the illness.

However, in some patients, the first sign of disease may be

mucocutaneous hyperpigmentation. Generalized bronzing

of the skin and diffuse but patchy melanosis of the oral

mucosa are hallmarks of hypoadrenocorticism. Any oral

surface may be affected.

In some patients, oral melanosis may be the first

manifestation of their adrenal disease. Diffuse

hyperpigmentation is more commonly associated with

chronic rather than acute-onset disease.

Endocrinopathic disease should be suspected whenever

oral melanosis is accompanied by cutaneous bronzing.

An oral biopsy typically shows increased melanin in the

basal cell layer with melanin incontinence. Thus, the

differential diagnosis includes other causes of diffuse

pigmentation, including physiologic and drug induced

pigmentation.

Laboratory tests, including the evaluation of serum cortisol

and electrolyte levels, are necessary to make a diagnosis

of addisonian hyperpigmentation.

Hyponatremia and hyperkalemia are frequently associated

with adrenal insufficiency. Treatment consists of exogenous

steroid replacement therapy. With appropriate therapy, the

pigmentation will eventually resolve.

Cushing’s Syndrome/Cushing’s Disease:

Cushing’s syndrome develops as a consequence of

prolonged exposure to relatively high concentrations of

endogenous or exogenous corticosteroids.

Most cases are iatrogenic in origin and associated with

poorly controlled or unmonitored use of topical or systemic

steroids. Cushing’s syndrome may also arise as a result of

various endogenous etiologies including an activating

pituitary tumor (Cushing’s disease) and a primary,

activating, adrenal pathology (hyperadrenocorticism), as

well as ectopic secretion of corticosteroids, ACTH, or

corticotropin-releasing hormone by various neoplasms,

including small cell carcinoma of the lung.

Overall, Cushing’s syndrome is more prevalent in female

patients. However, prepubertal onset is more commonly

seen in boys. Apart from the wide array of systemic

complications, including weight gain and the characteristic

“moon facies,” diffuse mucocutaneous pigmentation may

be seen in a subset of patients, specifically those whose

pathology is associated with increased ACTH secretion.

Thus, in most cases, the affected patients have a primary

pituitary neoplasm. The pattern of oral pigmentation is

essentially identical to that seen in patients with adrenal

insufficiency.

Serum steroid and ACTH determinations will aid in the

diagnosis and the pigment often resolves following

appropriate surgical, radiation, or medicinal therapy for the

specific source of the endocrinopathy.

Hyperthyroidism (Graves’ Disease):

Melanosis is a common consequence of hyperthyroidism(Graves’ disease), especially in dark-skinned individuals.

The pigmentation tend to resolve following treatment ofthe thyroid abnormality.

Primary Biliary Cirrhosis:

This uncommon disease is of unknown etiology,although it is thought to be autoimmune in nature.Primary biliary cirrhosis develops mainly in middle-agedwomen. The disease results from damage to smallintrahepatic bile ducts.

Primary biliary cirrhosis may also be a source ofgeneralize nonmelanocytic mucocutaneousdiscoloration.

Jaundice is usually an end-stage complication of primary

biliary cirrhosis. However, jaundice may also be

associated with a variety of other etiologies, including liver

cirrhosis, hepatitis, neoplasia, gallstones, congenital

disorders, and infection. Jaundice is caused by excessive

levels of serum bilirubin (a breakdown product of

hemoglobin). Hyperbilirubinemia often induces a

yellowish discoloration of the skin, eyes, and mucous

membranes. Treatment of the underlying disease will lead

to resolution of jaundice.

DD: carotenemia (excessive b-carotene) levels) and

lycopenemia (excessive lycopene, a compound

found within tomatoes and other fruits and vegetables).

However, the oral mucosal tissues are not affected in

either of these latter conditions.

Vitamin B12 (Cobalamin) Deficiency:

Vitamin B12 deficiency may be associated with a varietyof systemic manifestations, including megalobasticanemia various neurologic signs and symptoms, andvarious cutaneous and oral manifestations, including ageneralized burning sensation and erythema and atrophyof the mucosa tissue.

Diffuse mucocutaneous hyperpigmentation is rare, andpoorly recognized, complication of vitamin B1 deficiency.However, the pigmentation resolve following restoration ofvitamin B12 levels.

Peutz-Jeghers Syndrome:

Clinical manifestations include intestinal polyposis, cancersusceptibility, and multiple, small pigmented macules ofthe lips, perioral skin, hands, and feet.

The macules may resemble ephelides, usuallymeasuring <0.5 cm in diameter. However, theintensity of the macular pigment is notinfluenced by sun exposure. Althoughuncommon, similar-appearing lesions may alsodevelop on the anterior tongue and buccal andlabial mucosae. The lip and perioralpigmentation is highly distinctive, although notpathognomonic for this disease.

Other genetic diseases associated with a triadof gastrointestinal disease, cancer susceptibility,and mucocutaneou pigmented macules includeCowden syndrome and Cronkhite-Canadasyndrome.

Café au Lait Pigmentation:

Café au lait spots typically present as tan- or

brown-colored, irregularly shaped macules o

variable size. They may occur anywhere on

the skin.

Neurofibromatosis type 1:

development of multipl Neurofibromas,

Axillary and/or inguinal freckling (Crowe’s

sign) and pigmented lesions of the iris (Lisch

nodules)

McCune-Albright syndrome and Mazabraud

characterized by polyostotic fibrous dysplasia,

various endocrinopathies (McCune- Albright),

and soft tissue myxomas (Mazabraud disease).

In some patients, Addison’s disease or

Cushing’s syndrom may be a potential

consequence of McCune-Albrigh syndrome. The

café au lait spots in McCune-Albrigh syndrome

appear distinct from those associated with

neurofibromatosis. The borders of the pigmented

macules are irregularly outlined, whereas in

neurofibromatosis, the borders are typically

smooth.

Noonan’s syndrome and the allelic LEOPARDsyndrome (multiple lentigines,electrocardiographic-conductionabnormalities,ocular hypertelorism, pulmonary stenosis,abnormal genitalia, retardation of growth, andsensineural deafness) are associated withpigmented mucocutaneous macules andmultiple melanocytic nevi. The classic-appearing café au lait spots are morecharacteristically seen in patients with theNoonan’s phenotype. The LEOPARDphenotype is typically associated withnumerous, small, freckle-like macules ofteninvolving the facial skin.

Microscopically, when compared withadjacent uninvolved skin, genetic café aulait spots exhibit basilar melanosis withouta concomitant increase in the number ofmelanocytes. The melanocytes that arepresent demonstrate giant melanosomes(macromelanosomes) that may be visibleunder light microscopy. In contrast, whencompared with similar-appearing lesions inotherwise normal patients, genetic café aulait spots do exhibit increased numbers ofmelanocytes.

HIV/AIDS -Associated Melanosis:

Diffuse or multifocal mucocutaneous pigmentation.

The pigmentation may b related to intake of variousmedications, including antifungal and antiretroviral drugs,or as a result of adrenocortical destruction by virulentinfectious organisms.

HIV/AIDS patients may present with a history ofprogressive hyperpigmentation of the skin, nails, andmucous membranes. The pigmentation resembles mostof the other forms of diffuse melanosis. The buccalmucosa is the most frequently affected site, but thegingiva, palate, and tongue may also be involved.

HIV associated pigmentation is microscopicallycharacterize by basilar melanin pigment, withincontinence into the underlying submucosa.

Idiopathic Pigmentation:

Laugier-Hunziker Pigmentation:

Initially described as an acquired, idiopathic, macular

hyperpigmentation of the oral mucosal tissues specifically

involving the lips and buccal mucosae. Subsequent reports

detailed involvement of other oral mucosal surfaces, as well

as pigmentation of the esophageal, genital, and

conjunctival mucosae and the acral surfaces. Up to 60% of

affected patients also may have nail involvement, usually in

the form of longitudinal melanotic streaks and without any

evidence of dystrophic change. The fingernails are more

commonly affected than the toenails.

Laugier-Hunziker pigmentation is typically identified in adult

patients, with relatively equal sex predilection. This

condition more commonly develops in Caucasia or light-

skinned individuals.

Patients typically present with multiple, discrete,

irregularly shaped brown or dark brown oral macules.

Individual macules are usually no more than 5 mm in

diameter. In rare instances, the lesions may coalesce to

produce a diffuse area of involvement.

A differential diagnosis may include physiologic, drug- or

heavy metal–induced pigmentation, endocrinopathic

disease and Peutz-Jeghers syndrome.

Treatment of Mucocutaneous Melanosis:

In general, focally pigmented lesions warrant removal, forboth diagnostic and therapeutic purposes.

However, apart from those cases associated withneoplasia, surgical intervention is less of an option for thetreatment of multifocal or diffuse pigmentation.

Drug-induced melanosis and other examples ofexogenoausly stimulated generalized pigmentation mayspontaneously subside after withdrawal of the offendingsubstance.

Laser therapy has proven to be an effective modality for

use in the treatment of bothersome oral pigmentation.

Perioral and facial pigmentation: first-line therapy remainsthe application of topical medicaments, that is, bleachingcreams.

Although single agents such as azelaic acid or

hydroquinone have been used, more commonly, dual- or

triple-combination therapy is recommended.

Exogenous ochronosis is a form of intense cutaneous

hyperpigmentation with or without atrophic striae and

coarsening of the skin or formation of numerous

coalesced, black papules. This phenomenon is 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-brow pigmented

substance (not melanin) in the dermis. This

pigmentation may be permanent.

DEPIGMENTATION:

Vitiligo:

A relatively common, acquired, autoimmune disease that

is associated with hypomelanosis.

The pathogenesis of vitiligo is multifactorial, with both

genetic and environmental factors likely to play a role in

disease pathogenesis.

In most cases, vitiligo is characterized by bilateral,

symmetric areas of relatively generalized hypomelanosis.

As well-circumscribed round, oval or elongated, pale or

white-colored macules that may coalesce into larger

areas of diffuse depigmentation.

Most patients develop signs of the disease before the third

decade of life.

Vitiligo may also arise in patients undergoing

immunotherapy for the treatment of malignant melanoma.

Vitiligo rarely affects the intraoral mucosal tissues. However,

hypomelanosis of the inner and outer surfaces of the lips

and perioral skin may be seen in up to 20% of patients.

Microscopically, there is a complete loss of melanocytes

and melanin pigmentation in the basal cell layer.

Topical corticosteroids and topical or, more commonly,

systemic photochemotherapies (psoralen and ultraviolet A

exposure).

labial vitiligo is more resistant to the typical treatments used

for cutaneous vitiligo: surgical intervention

Hemoglobin and Iron- Associated Pigmentation:

Ecchymosis:

Traumatic ecchymosis is common on the lips and face yet

is uncommon in the oral mucosa, except in cases related

to blunt-force trauma and oral intubation.

If the patient recalls an episode o trauma, however, the

lesion should be observed for 2 weeks by which time it

should resolve.

Patients taking anticoagulant drug may present with oral

ecchymosis, particularly on the buccal mucosa or tongue,

either of which can be traumatized whil chewing.

Ecchymoses of the oral mucosa may also be encountered

in patients with liver cirrhosis, leukemia, and end-stage

renal disease undergoing dialysis treatment.

Laboratory tests: bleeding time, prothrombin time, partial

thromboplastin time, and international normalization ratio

Purpura/Petechiae:

Capillary hemorrhages will appear red initially and turn

brown in a few days once the extravasated red cells have

lyse and have been degraded to hemosiderin.

Petechia are typically characterized as being pinpoint or

slightly large than pinpoint and purpura as multiple, small

2 to 4 m collections of extravasated blood.

Viral disease is more commonly associate with oral rather

than cutaneous petechiae. In most cases the petechiae

are identified on the soft palate, although any mucosal

site may be affected.

When trauma is suspected, Within 2 weeks, the lesions

should resolve.

Causes of Oral Purpura/Petechiae:

Amyloidosis

Aplastic anemia

Bulimia

Chronic renal failure

Fellatio

Forceful coughing

Hemophilia

Henoch-Schönlein purpura

HIV/AIDS

Infectious mononucleosis

Leukemia

Liver cirrhosis

Nonspecific trauma

Oral intubation

Oral submucous fibrosis

Overexertion

Papular-pupuric “gloves and socks” syndrome

Streptococcal infection

Systemic lupus erythematosus

Thrombocytopenia

von Willebrand’s disease

Hemochromatosis:

A chronic, progressive disease that is characterized byexcessive iron deposition (usually in the form ofhemosiderin) in the liver and other organs an tissues.

Idiopathic, neonatal, blood transfusion, an heritable formsof this disease are recognized.

Complication of hemochromatosis may include livercirrhosis, diabetes anemia, heart failure, hypertension,and bronzing of the skin.

The oral pigmentation is often diffuse and brown to

gray in appearance. The palate and gingiva are mostcommonly affected.

Early on in the course of disease, the pigmentation maybe more commonly a result of basilar melanosis ratherthan iron-associated pigment.

Iron deposition within the adrenal cortex may lead to

hypoadrenocorticism and ACTH hypersecretion, with the

associated addisonian-type changes.

In the later stages of hemochromatosis, the pigmentation

is usually a result of hemosiderosis and melanosis.

A lower labial gland biopsy: Increased melanin pigment

may be seen in the basal cell layer, whereas golden or

brown-colored hemosiderin can be seen diffusely

scattered throughout the submucosa and salivary gland

tissues.

A Prussian blue stain will confirm the presence of iron.

Exogenous Pigmentation:

Amalgam Tattoo:

The single most common source of solitary or focal

Pigmentation in the oral mucosa.

Small, asymptomatic, macular, and bluish gray o even

black in appearance.

Gingiva, alveolar mucosa, buccal mucosa, and floor of

the mouth.

The lesions are often found in the vicinity of teeth with

large amalgam restorations or crowned teeth that

probably had amalgams, around the apical region of

endodonticall treated teeth with retrograde restorations or

obturated wit silver points, and in areas in and around

healed extraction sites.

Microscopically, amalgam tattoos often show a fine brown

granular stippling of reticulum fibers, with a particular

affinity for vessel walls and nerve fibers.

If there is no radiographic evidence of amalgam, the lesion

is not in proximity to any restored tooth, or the lesion

suddenly appears, a biopsy is necessary. A typical

differential diagnosis often include melanotic macule,

nevus, and melanoma.

Graphite Tattoos:

An unusual source of focal exogenous pigmentation. They

are most commonly seen as a solitary gray or black

macule on the palate and represent traumatic implantation

of graphite particles from a pencil.

Medicinal Metal-Induced Pigmentation:

Silver may cause a generalized blue-gray discoloration

(argyria), whereas gold-induced pigment may appear

blue-gray or purple (chrysiasis).

Chrysiasis doe not involve the oral mucosal tissues since

it is thought that exposure to ultraviolet light or other high-

intensity light sources precipitates the pigmentation.

Zinc- and medicinal silver-associated pigment is often

gray-black in appearance.

Generalized black pigmentation of the tongue has been

attributed to the chewing of bismuth subsalicylate tablets.

Discontinuation of the antacid and cleansing of

the tongue are curative.

Heavy-Metal Pigmentation:

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.

Thus, in the oral cavity, the pigmentation is a gray to black

appearance, usually found along the free marginal

gingiva.

Drug-Induced Pigmentation:

Minocycline, which is a tetracycline derivative and

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 pigmentationof developing teeth. When taken chronically, minocyclinemetabolites may become incorporated into the normalbone. Thus, whereas the teeth may be normal inappearance, the surrounding bone may appear green,blue, or even black. As a result, the palatal and alveolarmucosae may appear similarly and diffusely discolored.

Minocycline induced soft tissue pigmentation may appeargray, brown or black.

Microscopically, the particles are often intracellular andcontained within macrophages. Superficially, thesubmucosal pigment may resemble melanin and doesactually stain with what is thought to be a melanin specific(Fontana-Masson) histochemical stain. However an ironstain (Prussian blue) also highlights many of the sameparticles.

The discoloration often subsides within months afterdiscontinuation of the medication.

Hairy Tongue:

The change in oral flora associated with chronic

antibiotic therapy may be causative in some patients.

The discoloration involves the dorsal tongue, particularly

the middle and posterior one-third. The filiform papillae are

elongated and have the appearance of fine hairs.

The hyperplastic papillae then become pigmented by the

colonization of chromogenic bacteria, which can impart a

variety of colors, and posterior one-third. including white,

green, brown, or black.

Smoking of tobacco or crack cocaine has been associated

with black hairy tongue.

Treatments consist of having the patient brush the tongue,

or use a tongue scraper, and limit the ingestion of color-

forming foods and drinks until the discoloration resolves.