Oral Pigmentation: Causes and Diagnosis

• Oral pigmentation can be either focal, multifocal, or diffuse.
• The color of lesions may vary, appearing as blue, purple, brown, gray, or black.
• Some oral pigmentations are harmless and localized accumulations of melanin, hemosiderin, or exogenous metal.
• Other oral pigmentations are associated with systemic or genetic diseases, and even life-threatening medical conditions.
• A biopsy is a helpful and necessary aid in the diagnosis of focally pigmented lesions.
• More diffuse lesions necessitate a thorough history and laboratory studies to reach a definitive diagnosis.

Oral Pigmentation: Definition

• Oral melanin pigmentation can range from brown to black to blue, is dependent on the amount of melanin production and the depth of the pigment.
• Melanocytes are pigment-producing cells derived from neural crest cells.
• Melanin is formed from tyrosine through the action of tyrosinase.

Oral Pigmentation Etiology

• Oral pigmentation can be congenital or acquired.
• Oral pigmentation can be benign or malignant.
• Oral pigmentation can be endogenous or exogenous.
• Endogenous pigments originate within the body.
• Exogenous pigments are formed as a reaction to chemicals of exogenous origin.

Endogenous Pigmentation

• Hemoglobin, associated with vascular lesions, can produce blue, red, or purple discoloration which may indicate varix, hemangioma, Kaposi's sarcoma, angiosarcoma, or HHT.
• Hemosiderin, resulting from blood extravasation and hemoglobin degradation can result in brown discoloration indicative of ecchymosis, petechiae, varix, haemorrhage, mucocele, or hemochromatosis.
• Melanin, resulting from melanocyte hyperfunction or neoplastic transformation, can produce brown, black, or gray discoloration indicative of melanotic macule, nevus melanoma, or basilar melanoma.

Exogenous Pigmentation

• Accidental pigmentation.
• Iatrogenic pigmentation.
• Pigmentation related to drugs and metals.
• Localized pigmentation.

Causes of Oral Pigmentation

• Congenital causes include racial melanoplakia, naevi, and Peutz-Jegher's syndrome.
• Acquired causes include endocrinopathies, metabolic disorders like hemochromatosis, neoplastic conditions, metals, food/drugs such as oral contraceptives, antimalarials, minocycline, tranquilizers and AIDS

Benign vs. Malignant Oral Pigmentation

• Benign causes include physiologic pigmentation, oral melanotic macule, smoking melanosis, intraoral nevi, ephelides, and lentigo.
• Malignant causes include melanoma and neuroectodermal tumor of infancy.

Endogenous vs. Exogenous Causes

• Endogenous causes include post-inflammatory hyperpigmentation, melanoacanthoma, Addison's syndrome, and Peutz-Jegher's syndrome.
• Exogenous causes include drugs, amalgam tattoos, cultural or medical tattooing, tattoos, and heavy metals.

Investigations of Oral Pigmentation

• Involve gathering history of the present complaint.
• Obtain medical history, noting hypoadrenocorticism, pulmonary disease, and drug history.
• Examine social history for tobacco or betel nut habits and ethnicity.
• Perform extra-oral examination for evidence of cutaneous diseases.
• Conduct intra-oral examination to determine if pigmentation is localized or generalized.
• Measure blood pressure and serum electrolytes.
• Consider 24-hour urinary cortisol.
• Perform a Synacthen test.
• Obtain a biopsy.

Racial Pigmentation (Melanoplakia)

• Results in an increased amount of melanin pigmentation.
• Commonly seen in Blacks and Asians, and also in the Mediterranean region, but can occur in white individuals.
• Typically affects the attached gingivae, but can involve other oral sites.
• Exhibits variable color and extent and is usually asymptomatic.

Racial Pigmentation Differential Diagnosis:

• Addison's disease
• Albright's Syndrome
• Heavy metal pigmentation
• Use of antimalarial drugs

Labial & Oral Melanotic Macule

• There is an increase in melanin in the basal layer
• This is a common oral pigmentation
• Typically affects individuals aged 41–45, both sexes equally
• Occurs on the vermilion border of the lower lip, gingiva, palate and buccal mucosa of the mouth

Labial & Oral Melanotic Macule Characteristics

• Appears brown/brown black.
• Small, flat macules.
• Can appear as single or multiple spots.

Labial & Oral Melanotic Macule Differential Diagnosis:

• Amalgam tattoo
• Ecchymosis
• Nevi

Naevi Characteristics

• Typically occurs in young people ages 20 to 39 years.
• Sixty percent are intradermal naevi
• Approximately 25% are blue naevi.
• A nevus involves benign proliferation of melanocytes.
• It's most common as an intramucosal lesion (63-70%).
• More common on skin, rare in oral mucosa.
• Appears as a smooth nodule, hard palate is a common location.
• Lesions are usually elevated, palates are commonly affected, less than 1 cm in diameter and not premalignant.
• There are four types of naevi: Junctional, Compound, Intramucosal, and Blue.

Naevi: Additional Details

• Common in women (2/3rds of cases).
• Generally affects those 20-39 years old, averaging at 32 years.
• Observed mainly in the 3rd & 4th decades of life.
• Typically small, less than 1 cm in diameter.

Naevi: Differential Diagnosis

• Oral melanotic macule
• Retention cyst
• Hemangioma
• Early melanoma

Peutz-Jegher's Syndrome

• Presents with multiple pigmentation in the oral and perioral regions.
• Associated with gastrointestinal (GI) polyps, which can cause bleeding, anemia, and increased cancer risk.
• Increases risk of GI cancer, as well as lung and breast adenocarcinoma.

Peutz-Jegher's Syndrome: Clinical Features

• Affects both sexes equally.
• Associated with intestinal polyps.
• Causes abdominal pain.
• Characterized by bluish-black macules.
• Lesions typically range from 1-5 cm.
• Causes facial pigmentation.

Peutz-Jegher's Syndrome: Oral Manifestation

• Site of oral manifestation is the buccal mucosa, gingiva, tongue, and hard palate.
• Appears from birth.
• Multiple melanotic brownish macules around the lips.
• 0.5cm

Blue / Purple Vascular Lesions:

• Hemangioma
• Varix and Varices
• Hereditary Hemorrhagic Telangiectasia

Vascular Lesions Classifications:

• Hemangiomas
• Vascular Malformations:
  • High-flow Vascular Malformation:
    • AVMs arteriovenous malformations
    • AVFs arteriovenous fistulas
  • Low-flow Vascular Malformation
    • Venous Malformations
    • Lymphatic Malformations
    • Lymphatic Venous Malformations

Hemangiomas

• Usually absent at birth however can be congenital, will appear shortly after birth.
• Grows rapidly in infants up to 1 year.
• Usually involutes by the 3rd year.
• Histologically shows cellular hyperplasia

Vascular malformations

• Usually present from birth however may not be clinically apparent
• Growth proportional to body growth.
• Continues to grow
• Histologically has no hyperplasia; only single layer of endothelial cells

Hemangiomas Information:

• Usually first appear a few weeks after birth, and affect the head and neck in most patients.
• The trunk and extremities are less commonly involved.
• Appear like red, flat or raised, patches or plaques with or without a cluster of superficial veins.
• They are generally firm and rubbery to the touch.

Hemangioma Site:

• Tongue
• Lips
• BM / Palate

Hemangioma Color Determinants:

• Reddish blue indicates close proximity to the epithelium
• Blue indicates connective tissue involvement
• Flat reddish-blue macule indicates Port-wine stain

Hemangioma Medical Treatment Options:

• Systemic or intralesional steroids
• Systemic propranolol (dose of 1 to 3 mg/kg a day)
• Topical timolol, found to be useful in reducing size of infantile hemangiomas, especially near vital areas or with complications
• Interferon alpha 2a, a solution for large hemangiomas because it blocks migration and proliferation of endothelial cells, smooth muscle cells, and fibroblasts by decreasing the production of collagen and basic fibroblast growth factor. Dosage is 3 x 106 U/m²/day subcutaneously for 6-18 months.

Hemangioma Surgical Treatment Options:

• Laser
• Sclerotherapy
• Surgery
• Cryotherapy

More on Vascular Malformations:

• Arteriovenous malformations (AVMs) are generally present in neonates at birth but often manifest later due to various stimuli like trauma, pregnancy, or puberty.
• High-flow Vascular Malformations and Low flow vascular amlformation

Sturge-Weber Syndrome:

• Characterized by facial VM and intracranial vascular malformation of the arachnoid and pia mater meninges.
• Presents with intractable seizures, mental retardation, or glaucoma.

Vascular Malformations Treatment:

• Surgical treatment: Small, superficial arteriovenous malformations can be removed surgically
• Embolization - a process that closes off the arterial feeders of the malformation, is an effective method in arteriovenous malformations that stabilize the malformation.

Varix and Varices

• This is where a distended vein leads to a result from partial blockage of vein
• VARICES / VARICOSITY is pathological dilatation of vein or venules
• VARIX is a focal dilatation of group of venules or vein

Varices: Key Features

• Site: Ventral surface of tongue
• Age: Progressively prominent with age
• Color: Blue / Red / Purple elevations
• Margins & Shape: Sharply delineated borders & smooth.
• Symptoms: Painless
• Caviar Tongue: Many sublingual veins

Hereditary Hemorrhagic Telangiectasia

• Also known as Osler-Weber-Rendu disease and Osler-Weber-Rendu syndrome.
• A rare autosomal dominant genetic disorder that leads to abnormal blood vessel formation in the skin, mucous membranes, and often in organs such as the lungs, liver, and and brain
• Site: Vermilion border & mucosal surface of lips/ tongue/ BM
• Shape: Multiple round or oval papules that are 0.5 cm
• Color: Red or brown
• Management: Electrocautery

Freckle/Ephelis

• A cutaneous freckle, or ephelis is a commonly occurring, asymptomatic, small (1-3mm), well – circumscribed, tan-or brown-colored macule that is often seen in sun-exposed regions of the facial and perioral skin.
• Freckles tend to become darker during periods of prolonged sun exposure and less during the winter & autumn month.
• Ephelis is most commonly observer in light skin individuals and are quite prevalent in red or light blond-haired individuals and tend to reduce in number with age. Abundance & darker intensity are more noticeable during childhood and adolescence.

Lentigo

• Characterized as harmless (benign) hyperplasia of melanocytes with a linear spread, ranging from 2 mm to 2 cm, tan to dark brown
• Presents as a small pigmented spot on the skin with a clearly defined edge, surrounded by normal-appearing skin.
• In contrast to ephelides, lentigos are more common in older individuals and persist indefinitely, common on the face and may be seen in the perioral region.
• Variation in color or irregularity of outline should raise the suspicion of lentigo maligna (in-situ' melanoma).

Melanotic Macules

• Color: Brown or black
• Location: Usually the lips or gingivae
• Not typically premalignant, and arise at any age.

Melanoacanthoma

• Characterized as a benign, melanocytic lesion
• A reactive, but NOT neoplastic lesion
• Etiology unclear but possibly secondary to physical trauma.
• Presents as slightly elevated circumscribed solitary asymptomatic pigmented plaques.
• The term melanoacanthoma may imply a neoplastic process.
• They may spontaneously resolve, with or without surgical intervention, and may occur on buccal, palatal mucosa and gingiva or beneath the denture.
• Requires to be differentiated from Addison's disease.
• A biopsy is always warranted to confirm the diagnosis, but once established, no further treatment is required.

Smoker's Melanosis

• Diffuse melanosis of the anterior maxillary and mandibular gingivae, buccal mucosa, lateral tongue, palate, and floor of the mouth is occasionally seen among cigarette smokers.
• The mechanism by which smoking induces pigmentation is unknown.
• The oral melanosis increases in the first year of smoking and eventually it is reduced.

Tattoos

• Caused by intentional or accidental implantation of exogenous pigments into the mucosa
• Amalgam tattoos appear as blue-black, non-elevated discoloration that is usually irregular in shape and variable in size.
• Deterioration of the silver compounds of the amalgam imparts the characteristic color of the lesion.
• Can affect anywhere, but the gingiva is the favorable site.
• The clinical diagnosis can be confirmed by radiography otherwise failure of radiographic evidence necessitates biopsy to rule out more serious lesions.
• Other tattoos include graphite pencil wounds and India ink tattoos.
• Tattoos can reflect ritual (eg gingivae, lips)/lifestyle and are typically Harmless

Ecchymoses

• This is a type of discoloration of the skin resulting from bleeding underneath skin is typically caused by bruising

Local Causes of Oral Pigmentation

• Bacillary Angiomatosis
• Rare -Can be a feature of HIV disease -Caused by Bacteria called Bartonella henselae -Gives rise to pigmented nodules -Can affect the skin, bone and liver -Responds to erythromycin

Endocrinopathies Causing Oral Pigmentation

• Addison's disease
• Nelson's syndrome
• Ectopic ACTH production
• Pregnancy

Addisonian Pigmentation

• May arise with any cause of adrenocortical hypofunction (autoimmune, infection like TB, tumor).
• Typically involves the buccal mucosa.
• May be the only clinical features of adrenocortical hypofunction.
• The pigmentation is secondary to increased ACTH production by the anterior pituitary.
• Pigmentation is not specific to Addison's; however, if associated with candidal infection, endocrine studies should be performed.
• Brown or black color is seen in more than 75% of Addison's patients.

Addison's Disease: Clinical Features

• Caused by a chronic Adrenal insufficiency
• Bilateral adrenocortical destruction like:
  • TB / fungal
  • Bilateral tumor metastasis
  • Leukemic infiltration
  • Amyloidosis

Addison's Disease: Clinical Features / Oral Features

• Skin & MM pigmentation
• Cheek /Gingiva /Tongue /Lips
• Nausea/Vomiting/ Diarrhea & Anemia
• Bluish-black/ pale brown/ deep chocolate
• Skin turns a Bronze color

Addison's Disease: Differential Diagnosis

• Hyper pitutarism
• Hemochromatosis
• Adequate corticosteroid maintenance

Nelson's Syndrome

• A rare diseases where Excess ACTH production and pituitary expansion secondary to bilateral adrenalectomy for Cushing's disease occurs
• 10% develop oral pigmentation
• Oral pigmentation similar to Addison's disease

Ectopic ACTH Production

• A rare case where Excess ACTH is produced by bronchial adenocarcinoma
• Displays oral hypermelanotic pigmentation, a similar appearance to Addison's disease, and possible additional involvement of the soft palatal mucosa.

Chloasma

• Feature of late pregnancy
• Manifests as melanotic hyperpigmentation of the midface
• Involvement of the oral mucosa is extremely rare.

Albright's (McCune-Albright) Syndrome

• A rare non inherited genetic disease
• Polyostotic fibrous dysplasia,
• Sexual precocity,
• Cutaneous hyperpigmentation, Skin (café-au-lait macules)
• Occasional other endocrinopathies
• Possible melanotic hyperpigmentation of the oral mucosa (in addition to unilateral or bilateral fibrous dysplasia)

Hemochromatosis

• Deposition of excess iron (Ferritin & Hemosiderin) in body tissue
• Color:- Blue Gray Skin (Genital, face, arm
• Sex: 80% in men
• Causes:-
• Increased dietary iron intake
• Excessive blood transfusion

Hemochromatosis: Investigations

• Elevated serum iron, reduced TIBC, elevated ferritin
• Biopsy to identify iron in hepatocytes

Hemochromatosis: Complications

• Type I Diabetes (iron affects the functioning of the pancreas)
• Liver
• Cirrhosis
• Iron deposits in the pituitary and gonads lead to endocrine and sexual problems (hypogonadism, impotence, amenorrhea, infertility)
• Cardiomyopathy (iron deposits in the heart)
• Hepatocellular Carcinoma
• Hypothyroidism (iron deposits in the thyroid)
• Chondrocalcinosis / pseudogout (calcium deposits in joints) causing arthritis

Neurofibromatosis

• Neurofibromatosis, also known as Von Ricklinghausen's disease:
  • Triad→ Areas of pigmentation, sessile or pedunculated tumors of skin & mucous membrane & nerves
  • Tumors→ soft, smooth, fluctuant
  • Cafe au lait spots
  • There are two major types: - Neurofibromatosis type I (NFI), Neurofibromatosis type II (NF2) -Neurofibromatosis also causes pigmentations on mucosa, lips. JAWS→ Intrinsic bone formation. Also causes radio graphic abnormalities like Central cyst like radiolucency and Irregular area of bone destruction

Pigmentary Incontinence

• Uncommon
• Usually arises in late age in association with oral lichen planus
• Patients are often tobacco smokers
• Areas of melanotic pigmentation in the site of a present or past Lichen Planus can exclude Addison's disease, usually asymptomatic

Drug-Induced Oral Mucosal Pigmentation: Colors

• Blue
• Brown
• Black
• Grey
• Green

Drug-Induced Oral Mucosal Pigmentation: Blue

• Amiodarone
• Antimalarials
• Bismuth (overdose)
• Minocycline
• Quinidine
• Silver
• Sulphasalazine

Drug-Induced Oral Mucosal Pigmentation: Brown

• Busulphan
• Cyclophosphamide
• Fluorouracil
• Doxycycline
• Clofazimine
• Oral contraceptives
• HRT
• Ketoconazole
• Menthol
• Minocycline
• Propanolol
• Zidovudine
• Heroin

Drug-Induced Oral Mucosal Pigmentation: Black

• Amiodaquine
• Methyldopa

Drug-Induced Oral Mucosal Pigmentation: Green

• Copper

Drug-Induced Oral Mucosal Pigmentation: Grey

• Chloroquine
• Fluoxetine
• Hydroxycholoquine
• Lead
• Silver
• Tin/zinc

Malignant Causes of Oral Pigmentation

• Local causes of oral pigmentation Malignant Melanoma
  • Melanoma - malignant tumors of nevus cells
  • Oral MM is rare, in a male : female ratio of 2:1, mostly affecting persons >50 years of age
  • Often affects the palate, maxillary alveolar ridge, anterior gingiva and labial mucosa, but can involve other oral sites
  • Oral lesions may be primary or secondary tumors
  • Localized brown or black macule, papule, or nodule, often with ulceration and destruction
• Early diagnosis is an asymmetric lesion, with border irregularity, color variation, and diameter enlarging,

Malignant Melanoma Early and Late Signs

• Early recognizable signs: asymmetric lesion, border irregularity, color variation, and diameter enlarging
• Late signs: bleeding and ulceration, firmness on palpation and rock-hardregional lymph nodes

Malignant Melanoma Early Signs

• Early diagnosis, when tumors are less than 1.5 mm in diameter and complete resection are critical to long term survival, can result in a poor outcome

Oral Melanoma Presentations

• Pigmented macule
• Pigmented nodule
• Large pigmented exophytic lesion
• Amelanotic variety
• May ulcerate- but no rolled out borders.

Signs of Oral Melanoma: ABCDE's

• Asymmetry, one side is different from the other
• Border is irregular, notched, or blurred
• Color is mixed
• Diameter is larger than 6 millimeters
• Mole Evolves over time

Oral Melanoma Characteristics

• Has a slow rate of growth
• The vertical phase- is Rapid
• Usually Painless
• Has a rapid infiltration
• Spread through lymphatic & hematogenous routes
• Many develop from Navi

Oral Melanoma: Differential Diagnosis

• Oral melanotic macule
• Amalgam tattoo
• Nevus
• Focal hemosiderin deposit

Kaposi Sarcoma: Characteristics

• A common neoplasm in HIV pt's Site→ Posterior hard palate / Multifocal Nodular growth, Protruding below the occlusal plane:
• Cutaneous has a Red macule that becomes blue, purple & brown nodular - Oral: Flat red macule Treatment is Electrocautery Electrocautery

Angiosarcoma

• A malignant vascular neoplasm Rapidy proliferates in a Nodular fashion that is superficial. Superficial Coloration can be Red, Blue or Purple nodular tumor.

Melanotic Neuroectodermal Tumor of Infancy: Features

• A Rare, rapidly growing, pigmented neoplasm of neural crest origin, affects the maxilla of infants during the first year of their life. Gender predilection is not described. 90% arises in the head and neck
• Clinically, lesions are soft and rapidly growing pigmented swellings. They often destroy the underlying bone and may be associated with displacement of developing teeth.

-Benign and a rapidly destructive tumor. But (6.5%) malignant.

• Treatment: Surgical excision