# Oral Medicine and Oral Pathology/Pigmented lesions of the oromucosa

Discoloration of the oral mucosa by pigment occurs with many different conditions, which may be otherwise totally unrelated in many other respects. The color of oral mucosa depends upon the epithelial thickness, the keratin status, the vascularity, and the density of the underlying fibrous tissue/hard tissue. Lesions like erosions (shallow ulcers) will lead to epithelial thinning and the red color of the vascularized tissues underneath showing through more readily. Deeper ulceration into the lamina propria may be red at first due to hemorrhage, but quickly the epithelial breech is covered with fibrin and a more yeallow-grey color develops. Similarly, hyperkeratosis will lead to thickening of the epithelium, and cause the red colour of the underlying tissues to show through less readily. Instead, the excess keratinized cell layers give a whitish color. When there is increased vascularity of the underlying tissues, as occurs in many inflammatory and/or infectious lesions, then the mucosa may appear erythematous (literally, "red"). Conversely, in cyanosis, the underlying tissues will be less well perfused with oxygenated blood, and the mucosa may appear cyanotic (blue or purple). Pigments may be endogenous or exogenous. Endogeneous pigments are produced by the body's own metabolism, whereas exogenous pigments enter the body from the external environment. The mucosa may also be affected surface stains, e.g. tobacco, iron lozenges, or may be colonized by chromogenic bacteria (e.g. as in black hairy tongue, see image).
* Oral Med/Oral Path
* School of Medicine
* School of Dentistry

## Endogenous pigments

These include melanin, bilirubin and hemosiderin. The most important is melanin (Gr. melas - "black"), which is synthesized by melanocytes in the basal epithelial layer and then transferred to keratinocytes. Generalized increased activity of melanocytes may occur in systemic disease, most notably Addison's disease. It may also occur locally as a component of other mucosal lesions (e.g. lichen planus, response to smoking or with HIV infection). Causes of increased melanin pigmentation (melanosis) can be classified in 3 groups:
* Associated with proliferation of melanocytes
      * Melanocytic naevi
      * Malignant melanoma
      * Melanocytic neuroectodermal tumor of infancy (pigemented epulis)
* Associated with melanocyte colonisation of non-melanocytic tumors
      * Basal cell cercinoma
      * Squamous cell carcinoma
* Occurring in the absence of melanocytic proliferation
      * Iatrogenic, e.g. effect of medications (chlorpromazine, used in schizophrenia, and antimalarials)
      * Postinflammatory hyperpigmentation (lichen planus)
      * Endocrine influences (chloasma of pregnancy, Addison's disease)
      * Genetically determined diseases (neurofibromatosis, Peutz-Jegher syndrome, Albright's syndrome)
      * Melanotic macule (ephelis)
Bilirubin pigement is deposited in the mucosal tissues, especially the palate, in bilirubinemia. Bilirubinemia may be hepatogenic, cholestatic or hemolytic.
Hemosiderin is an insoluble form of iron. It can usually be found withing macrophages. Causes of increased hemosiderin pigmentation may be localized (bruising, giant cell granuloma, radicular cyst), or generalized as part of a systemic hemochromatosis ("bronze diabetes").

## Exogenous pigments

The most common lesion caused by exogenous pigments is the amalgam tattoo. Other heavy metals can be systemically introduced (e.g. Bismuth, silver, mercury or gold).

## Diagnostic approach

As usual, a history and examination are important. The following information may be important:
* Color of lesion
* Site
* Shape
* Margins
* Flat (macule) or raised (nodule)
* sessile or pedunculated
* Blanching with pressure
* Distribution: focal (i.e. only one) or generalized (more than one lesion)
* Patient age
* Systemic symptoms (malaise, fatigue, weight loss)
* Medications
* Smoking status
In general, benign pigmented lesions have regular margins and are small symmetrical and have uniform color. They may be macular or slightly raised. Conversely, possible features of a malignant pigmented lesion are irregular margins, color variation and surface ulceration. An algorithm for evaluation of pigmented lesions of the oral cavity was proposed by Kauzman et al and is shown below. Some of the more notable pigmented lesions are discussed individually.

## Physiologic (racial) pigmentation

Physiologic pigmentation is observed in all racial groups, but to varying degrees. Interracial differences in skin pigmentation are largely the result of differences in melanin activity and the amount of melanin contained in keratinocytes, with the numbers of melanocytes varying little between races. It may be more pronounced in individuals of african, asian and mediterranean ethnic descent. The numbers of melanocytes of an individual vary according to body site, age and exposure to sunlight. These areas of light to dark brown pigmentation are asymptomatic, symmetrical and and usually sited on attached gingiva (but sparing the marginal gingiva) and buccal mucosa. Less commonly, hard palate, lips and tongue may also be affected, but with less well defined brown patches. Physiolgoic pigmentation develops within the first 20 years of life. No treatment is indicated. If pigmented gingivae are surgically resected or lacerated, healing occurs with little or no pigmentation, making scaring more visible.

## Peutz-Jeghers syndrome

This is a rare genetic disorder characterized by cutaneous (especially circumoral) melanotic macules, intestinal hamartomatous polyposis and and a generalized increased risk in cancer (including small intestine, colon, gastric, pancreas, breast and genital tract). The intestinal polyps can involute and cause a bowel obstruction (a surcial emergency). The 1-10mm diameter melanotic spots are obvious periorally, and may also occur on the extremities and on the mucous membranes of the oral cavity, nasal cavity, conjunctiva and rectum. The melanotic macules themselves are not associated with increased risk of melanoma, however long term review may be indicated incase of development of internal malignancies.

## Addison's disease

Primary hypoadrenalism is due to progressive bilateral destruction of the adrenal cortex by autoimmune disease, infection or malignancy. A decreased level of adrenocortical hormones in the blood stimulates ACTH production in the anterior pituitary. Increased ATCH induces melanocyte-stimulating hormone, resulting in diffuse pigmentation of the skin and oral mucosa. Intraorally, this presents as brown patches on the gingiva, buccal mucosa, palate and tongue. These lesions may resemble racial pigmentation, but they develop during adult life and are progressive. Addisons may give systemic manifestations such as weakness, nasea, vomiting, abdominal pain, constipation or diarrhea, weight loss and hypotension. Diagnosis is with ACTH levels, plasma cortisol and serum electrolytes. Addison's may be fatal if left untreated, and oral pigmentation may be the first sign. Oral biopsies show acanthosis with silver positive intracellular granules in the stratum germinativum and melanin in basal layer. Management is cause related and corticosteroid replacement therapy.

## Hemachromatosis

This is a chronic disease characterized by deposition of excess iron (ferritin and hemosiderin) in tissues, resulting in fibrosis and functional insuffiency of the involved organs. There may be hyperpigmentation of skin and mucous membranes, with 15-25% of patients showing pigmentation of gingival or mucosal pigmentation. These areas are duffuse, homogenous grey brown or deep brown in about 20% of cases.

## Heavy metal pigmentation

Lead, bismuth, mercury, silver, arsenic and gold present in the blood can cause oral mucosal pigmentation. In adults, occupational exposure to heavy metal vapours is the most common cause, and in children lead contaminated water, paint and mercury - or silver-containing drugs. Historically, some diseases were treated with heavy metal containing drugs, e.g. syphylis. The pigmentation presents as a blue-black line along the gingival margin, but other sites may be involved. Depending upon the metal implicated, a number of different systemic signs and symptoms may be associated with chronic exposure. The Bismuth line is a blue-black pigmentation for the marginal gingiva. Historically, this would appear in syphlytic patients treated with bismuth compounds. Lead intoxication (plumbism) can lead to a similar line (Burton's line).

## Kaposi's sarcoma

This is a multifocal vascular malignancy seen mostly in HIV infected patients. Appearance of kaposi's sarcoma is considered a heralding event for progression to AIDS. The cause is human herpesvirus 8, and the lesion most commonly occurs on the hard palate, gingiva and tongue. Early lesions are macular, brown to purple and often bilateral. Advanced lesions are dark red to purple plaques or nodules with or without ulceration, bleeding and necrosis. Biopsy shows a proliferation of spindle shaped cells surrounding poorly formed vascular spaces or slits with numerous extravasated erythrocytes.

## Drug induced pigmentation

* Drugs causing oral pigmentation
* Antimalarials (quinacrine, chloroquine,
* hydroxychlorquine)
* Quinidine
* Zidovudine (AZT)
* Tetracycline
* Minocycline
* Chlorpromazine
* Oral contraceptives
* Clofazimine
* Ketoconazole
* Amiodarone
* Busulfan
* Doxorubicin
* Bleomycin
* Cyclophosphamide
* 5-Fuorouracil
This can be caused by accumulation of melanin, deposits of the drug or its metabolites, synthesis of pigments under the influence of the drug or deposition of iron after damage to the dermal vessels. Chlorquinine and other quinine derivatives (antimalarials, also used in cardiac arrhythmia and in discoid lupus erythematosus and rheumatoid arthritis) are known to give rise to blue-grey or blue black mucosal pigmentation, usually only on the palate. These drugs produce a direct stimulatory effect on melanocytes. Minocycline (a synthetic tetracycline used in acne) can cause pigmentation of the alveolar bone, which can be seen through the thin overlying oral mucosa (especially the maxillary anterior alverolar mucosa) as a grey color. This drug can also cause pigmentation of the tongue.

## Postinflammatory pigmentation

Long standing inflammatory disease, especially lichen planus, can cause pigmentation. This is seen more in dark skin types. Multiple dark brown-black pigmented areas may be seen adjacent to reticular or erosive lichen planus lesions. Histologically there is increased production of melanin by melanocytes and accumulation of melanin in macrophages in the superficial connective tissue.

## Smoker's Melanosis

Increased production of melanin may provide a biologic defence against the noxious agents in cigarette smoke. Smokers melanosis occurs in up to 21.5% of smokers. Lesions are brown-black and most often on the anterior labial gingiva, followed by the buccal gingiva. The pigmentation is related to the duration and level of smoking, and women are more commonly affected than men. This melanosis usually disappears within 3 years of cessation.

## Hemangioma and vascular malformation

A hemangioma is a benign proliferation of endothelia that line blood vessels. Vascualr malformation is a structural abnormality of blood vessels without endothelial proliferation. Both lesions have an onset during infancy. Hemangiomas regress as the the patient ages, but vascular malformation persists throughout life. Intraorally, the tongue is the most common site. The lesion is flat or slightly raised and colored red to bluish purple (depends on whether capillaries, veins or arteries involved and the depth of the lesion in the tissues). Upon applying pressure with a transparent surface (diascopy), there is usually blanching, but lack of blanching does not exclude the possibility of a vascular lesion.

## Varix and thrombus

Varices are abnormally dilated veins, usually seen in patients aged 60 + on the ventral tongue. Here, varices appear as multiple bluish purple irregular, soft elevations which show a positive result with diascopy. Thrombi are more common on the lower lip and buccal mucosa. If a varix contains a thrombus, the lesion is firm bluish-purple and does not show blanching.

## Hematoma and other hemorrhagic lesions

Petechiae (< 0.3 cm), purpurae (0.3–1 cm) and ecchymoses (>1 cm) are terms to describe different sized lesions formed by a common process, i.e. subcutaneous (or submucosal) bleeding which spreads out in a thin layer beneath the skin. The lesions are non blanching, red or purple discolorations. Although often eroniously used as a synonym for bruising, ecchymosis may not be caused by trauma. A hematoma is a localized collection of extravasated blood, in contrast to the aforementioned lesions which are created by blood in a thin subcutaneous layer. Hematomas may be superficial, where the term contusion can be used, or present in deeper tissues, e.g. intramuscular. These lesions may occur with systemic coagulopathy and/or trauma, but hematomas and contusions by definition result from trauma. The color is produced by the degradation of hemoglobin to bilirubin and bilirubin, and progresses from red, purple, blue and bluish black depending upon the age of the lesion. Return to normal coloration can take up to 2 weeks.

## Amalgam tattoo and other foreign-Body pigmentation

An amalgam tattoo is a localized, blue-grey lesion of variable dimensions most commonly sited on the gingiva or alveolar mucosa, or less commonly the floor of mouth or buccal mucosa. Amalgam tattoo is on of the most common causes of intraoral pigmentation. The lesion does not disappear with pressure, and there is no signs of inflammation at the periphery of the lesion. If the deposits of amalgam in the tissues are large enough, they may be show up radiographically as radiopaque debris in the soft tissues or superimposed on hard tissue.
Graphite can be introduced into the oral mucosa through accidental injury with a graphite pencil. This lesion is an irregular grey-black maccule, most commonly on the anterior palate of young children.

## Melanotic maccules

This is a benign pigmented lesion commonly sited on the lower lip (they are not known to transform to melanomas). These lesions can also occur within the oral cavity, commonly gingiva, buccal mucosa or palate. The cause increased melanin production with no increase in melanocyte number. Melanotic maccules are usually light or dark brown and smaller than 1 cm and show a well demarcated border non irregular border. The color is homogenous within each lesion. These are more common in women and young adults. Biopsy may be indicated to rule out melanoma, and no treatment is otherwise indicated.

## Pigmented nevi

These are rare causes of focal pigmentation in the oral cavity. They are blue or brown lesions, histologically there is an accumulation of nevus cells in the basal epithelial layer, the connective tissue, or both. These yield the classification junctional, intradermal, intramucosal and compound nevi.