Oral Pigmentation

ORAL PIGMENTATION

• INTRODUCTION

• CLASSIFICATION

• ENDOGENOUS PIGMENTATION

• EXOGENOUS PIGMENTATION

• DRUG RELATED PIGMENTED LESIONS

• ASSOCIATED SYNDROMES

• MISCELLANEOUS

- HIV INFECTIONS

- NEVI OF OTA

• DEPIGMENTATION

• WORKUP

INDEX

PIGMENT • Color or Coloring Agent

NORMAL MUCOSA• Pale pink to deep bluish purple

sometimes even blackish

NORMAL RANGE DEPENDS UPON

Melanogenesis and distribution of melanin pigment

Keratinization

Depth of epithelization

Vascularity

Melanin

= primary pigment producing brown coloration

• Tyrosine – tyrosinase –melanin- this occurs in the melanosomes of melanocytes

• Then the melanosomes are transferred from the melanocyte to a group of keratinocytes called the epidermal melanin unit

• Variations in skin color is related to the number of melanosomes, the degree of melanization, and the distribution of the epidermal melanin unit

FACTORS AFFECTING MELANOGENESIS

Increased sun exposure

Drugs

Hormones

Genetic constitution

MelanocytesTyrosine

(tyrosinase)Melanin

Transfer –adjacent basal

cells

Damaging effects of

actinic radiations

Overproduction Over population

Sun exposure, drugs, hormones Benign nevi, malignant melanoma

CLASSIFICATION

1. ENDOGENOUS PIGMENTATION

2. EXOGENOUS PIGMENTATION

3. DRUG RELATED PIGMENTED LESIONS

4. ASSOCIATED SYNDROMES

5. MISCELLANEOUS

- HIV INFECTIONS

- NEVI OF OTA

ENDOGENOUS PIGMENTATION

PIGMENT COLOR DISEASE PROCESS

MELANIN BROWN/ MELANIN MACULE, NEVUS,

BLACK/GREY MACULE

HEMOSIDERIN BROWN ECCHYMOSIS,PETECHIAE,

VARIX, HEMOCHROMATOSIS

HAEMOGLOBIN RED/BLUE/ VARIX, HEMANGIOMA, KAPOSI’S PURPLE SARCOMA, HEREDITARY

HAEMORRAGIC TELANGIECTASIA

CAROTENE YELLOW CAROTENEMIA & JAUNDICE LIPOFUSCHIN

EXOGENOUS PIGMENTATION

SOURCE COLOR DISEASE PROCESS

SILVER AMALGAM GREY/ TATTOO, IATROGENIC TRAUMA BLACK

GRAPHITE GREY/ TATTOO, IATROGENIC TRAUMA BLACK

LEAD, BISMUTH, GREY INGESTION OF PAINTS, DRUGSMERCURY

CHROMOGENIC BLACK/ SUPERFICIAL COLONIZATIONBACTERIA BROWN/ GREEN

PIGMENTED LESIONS

Diffuse & bilateral Focal

Early onset Adult onset

Non • blanching

No systemic

Systemic Blanching

Red-blue-purple Blue-grey Brown

-Physiologic

-Peutz- Jeghers synd

•Addisons disease•Heavy metal •Kaposi’s sarcoma

• Drug induced• Post inflammatory • Smokers melanosis

•Melanotic macule•Pigmented nevus•Melanoma•Melanoacanthoma

•Thrombus•Hematoma

•AmalgamTattoo•Foreign Body tattoo•Blue nevus

•Varix•Hemagioma

Adel Kauzman, Marisa Pavone, Nick Blanas. Pigmented Lesions of the Oral Cavity: Review, Differential Diagnosis, and Case Presentations. Journal of the Canadian Dental Association. November 2004, Vol. 70, No. 10

DRUG RELATED PIGMENTED LESIONS QUININE & OTHER ANTIMALARIAL DRUGS

MINOCYLINE

ORAL CONTRACEPTIVES

ASSOCIATED SYNDROMES PEUTZ JEGHER’S SYNDROME

ADDISON’S DISEASE

ALBRIGHT SYNDROME

NEUROFIBROMATOSIS

MISCELLANEOUS LESIONS HIV INFECTION

HAIRY TONGUE

NEVI OF OTA

CLINICAL CLASSIFICATION OF ORAL PIGMENTATION

COLOR SOLITARY MULTIFOCAL FOCAL DIFFUSE

BLUE/ VARIX, HEMANGIOMA KAPOSI’S SARCOMA

PURPLE HEMANGIOMA HEREDITARY HAEMORRAGIC TELANGIECTASIA

BROWN MELANOTIC ECCYMOSIS PHYSIOLOGIC

MACULE, MELANOMA LICHEN PLNUS

NEVUS DRUGS DRUG INDUCED

MELANOMA HAIRY TONGUE ADDISON’S

PETECHIAE PEUTZ JEGHER’S ALBRIGHT’SGREY/ AMALGAM AMALGAM HEAVY METAL

BLACK GRAPHITE HAIRY TONGUE INGESTION

NEVUS

MELANOMA

ENDOGENOUS PIGMENTATION ORIGINATES FROM WITHIN THE BODY

A) MELANIN PIGMENTATION: ‘MELAS’– BLACK

Endogenous, non haemoglobin derived brown black pigment

formed when the enzyme tyrosinase mediated by MSH from

anterior pituitary catalyses the oxidation of tyrosine to

dihydroxyphenylalanine in melanocytes that subsequently

transfer the melanin into adjacent cells.

COLOR— Pale Brown to Black depending on the amount of melanin

• Number of melanocytes are equal in fair and dark skinned people, only the level of melanogenesis varies

ORAL MELANOACANTHOMA• It another unusual, benign, melanocytic

lesion that is unique to the mucosal tissues.

• Its an innocuous melanocytic lesion that may spontaneously resolve, with or without surgical intervention.

• Reactive in nature• Almost exclusively occurs in blacks &

has a female predilection.

EPHELIS (EPHELIDES/FRECKLES)

ORAL MELANOTIC MACULE :

Oral counterpart

Usually a solitary lesion occurs mostly in light skinned people

Lesion is well circumscribed and grey, brownish black

Majority being less than 1cm in diameter & remains constant in size

Most common site is lower lip followed by gingiva, buccal mucosa and hard palate

Asymptomatic and don't tend to become malignant

Occur equally in men and women, rarely in children

Pigmentation is due to increase in melanin pigment by basal cell melanocytes without increase in melanocytes

BROWN MELANOTIC LESIONS

HISTOPATHOLOGICALLY :

Normal epithelial layer with basal cell containing numerous melanin

pigment granules without proliferation of melanocytes

DIFFERENTIAL DIAGNOSIS:

Melanoplakia,

Amalgam Tattoo,

Nevi,

Focal

Ecchymosis,

Early superficial spreading melanoma

• Biopsy• melanin-containing dendritic cells are seen to extend

high into a thickened spinous layer. melanoacanthoma• Surgery –no predisposition to melanoma• Myxoma syndrome-soft tissue myxoma +

endocrinopathy (autosomal dominant)• Laugier –Hunziker syndrome/phenomenon-acquired

disorder + lips, oral, finger+ subungual melanocytic streaks

NEVOCELLULAR AND BLUE NEVI :

Unlike ephelis or melanotic macule, nevi are due to benign proliferations of melanocytes

Histologically they are of two types

i) NEVOCELLULAR NEVI JUNCTIONAL NEVI

Resides at the junction of epithelium and basement membrane.

Flat and brown and have regular round or oval outline.

Arises in early in life

INTER MUCOSAL NEVI

Melanocytes lose their continuity with surface epithelium & become localized to connective tissue.

• Benign proliferations of melanocytes Nevus cells - localized to basal layer- junction of

epithelium and basement membrane+ connective tissue

Minimal proliferation

Macular, flat and brown, regular outline

Junctional nevi

Melanocytes form clusters at the epitheliomesenchymal junction

proliferate down into the connective tissue

Dome shaped appearance

Compound neviLose their continuity with surface epithelium+

cells become localized - deeper connective tissues

Intradermal nevi (skin)Intramucosal (mouth)

INTRADERMAL NEVI

COMPOUND NEVI

JUNCTIONAL NEVI

INTRAMUCOSAL NEVUS- appears as brown and black elevated papules

II) BLUE NEVI :Not derived from basal layer.

Blue in color because the melanocytic cells resides deep in connective tissue and overlying vessels dampens the brown colorations and yield a blue tint.

Differ morphologically from nevocellular by being more spindle shaped.

May be seen at any age

May be macular or nodular.

Both nevocellular and blue nevi are less than 0.5 cm in size.

Occur most commonly on gingiva or hard palate, also on buccal mucosa and lips.

Biopsy- MUST.

Treatment – Surgical Excision.

COMPOUND NEVUS

• Round oval shape, well- demarcated,

• Smooth – bordered,

• May be dome–shaped or papillomatous;

colors range from flesh colored very dark

brown with individual nevi being relatively

homogeneous in color.

COMPOUND NEVUS

HISTOPATHOLOGY OF NEVI

Microscopically, the nest of nevi cells is laden with melanin and is seen below the basal cell layer (intramucosal nevus), at the junction of basal layers (junctional nevus), in both sites (compound nevus), or deep in the connective tissue (blue nevus). Excision of these lesions is required to rule out other serious pigmented lesions.

INTRAMUCOSAL NEVUS

JUNCTIONAL NEVUS

COMPOUND NEVUS

BLUE NEVUS

MALIGNANT MELANOMA

Melanomas arises from neoplastic transformation of either

melanocytes or nevus cells

Predisposing factors :

- sunlight, degree of nature pigmentation and precancerous

lesions such as junctional nevi

Clinically appears as macular or nodular,

Coloration varies ranging from brown black to black with zones

of depigmentation with jagged and irregular margins

Commonly occurs on anterior labial gingiva and anterior aspect

of hard palate

TYPES

• Superficial spreading melanoma• Nodular melanoma• Lentigo maligna melanoma• Acral lentiginous melanoma• Mucosal lentiginous melanoma• Amelanotic melanoma

RISK FACTORS FOR CUTANEOUS MELANOMA

• Large number of typical moles• Atypical moles• Family H/O melanoma• Prior melanoma• Freckling• H/O repeated blistering sunburns• Ease of sunburning• Inability to tan• Light hair and blue eyes

Oral melanomas are extremely rare• May be focal or diffuse Occur as macular brown or black plaques with

irregular margins • Biopsy is required for diagnosis

SUSPICIOUS CHANGES IN NEVI

SYMMETRY

ORDER IRREGULARITY

OLOR VARIEGATION

IAMETER GREATER THAN 0.6 cm

LEVATIONGondivkar SM, Indurkar A, Degwekar S, Bhowate R. Primary oral malignant melanoma- A case report and review of literature. Quitessence International. 2009; 40(1): 41-46.

“Lentigo maligna melanoma” or “hutchinson’s freckle”

Facial skin lesions – atypical melanocytic hyperplasia /melanoma in situ.

Melanocytic tumor cells spread laterally and superficially

Radial growth phase

Good prognosisNodular-deeper invasion-vertical growth-poor

• Breslow method, by which millimeter

depths of invasion are measured (depth

correlating with prognosis

• Oral mucosa -anterior labial gingiva,

anterior hard palate.

• They may be focal or diffuse and mosaic

Staging

• Stage I-primary tumor only (T any No Mo)• Level I- melanoma in situ without evidence of

invasion/microinvasion present• Level II-invasion upto lamina propria• Level III- deep skeletal tissue-muscles• Stage II- metastatic to regional lymph node (T any

N1 Mo)• Stage III- distant node metastasis (T any Nany M1)

Gondivkar et al. Primary malignant melanoma-case report & review of literature.quitesscence int vol 7; jan 2009

• The American Joint Committee on Cancer does not have published guidelines for the staging of oral malignant melanomas. Most practitioners use general clinical stages in the assessment of oral mucosal melanoma, as follows:

• Stage I - Localized disease• Stage II - Regional lymph node metastasis• Stage III - Distant metastasis

• Tumor thickness and lymph node metastasis are reliable prognostic indicators. Lesions thinner than 0.75 mm rarely metastasize, but they do have metastatic potential. On occasion, a small primary lesion is discovered after an enlarged lymph node is found to harbor melanoma.

Tumor Depth Approximate 5 year survival

<1 mm 95-100%1 - 2 mm 80-96%

2.1 - 4 mm 60-75%>4 mm 50%

DDxCONDITION DISTINGUISHING CHARACTERISTICS

Seborrheic keratosis “Stuck-on appearance”, symmetric often multiple

Traumatized or irritated nevus Returns to normal appearance within 7-14 days

Pigmented basal cell carcinoma Waxy appearance, telangiectasias

Lentigo Prevalent in sun-exposed skin, evenly pigmented, symmetric

Blue nevus Darkly pigmented from dermal melanocytes, no h/o change

Angiokeratoma Vascular tumors, difficult to distinguish from melanoma

Traumatic hematoma May mimic melanoma but resolves in 7-14 days

Venous lake Blue, compressible, found on ears and lips

Hemangioma Compressible, stable

Dermatofibroma Firm growths of fibrous histiocytes, ‘button-hole’ when pinched

Pigmented actinic keratosis Sandpapery feel; sun-exposed area

TREATMENT

• Excision with wide margins• CT & MRI-Rule our metastases-submandibular

& cervical nodes• Immunosuppressive drugs

Treatment protocol for malignant melanoma

Surgery Surgery and combined therapy OthersCancer/testis antigens(CTAs) expressionprofile for vaccinedevelopmentGene therapyOK432 (a biologicresponse modifier)

Radiotherapy Chemotherapy Immunotherapy

Curative chemotherapyDimethyl triazeno imidazolecarboxamide (DTIC)Nimustine hydrochloride (ACNU)Vincristine (VNC)

Palliative chemotherapyDacarbazinePlatinum analogsNitrosoureasMicrotubular toxins

IL-2

Other cytokines

Pai A, Prasad S, Patil BA, Dyasanoor S, Hegde S. Oral pigmentation: Case report and review of malignant melanoma with flow charts for diagnosis and treatment. General Dentistry. 2012; 410-416.

MELANOMA MEDICAL THERAPY

• Medical therapy is not often beneficial for oral melanoma. Chemotherapeutic medications for the treatment of oral melanoma do not reliably reduce the tumor volume.

• Aggressive surgery remains the treatment of choice.• Interferon, dacarbazine, and BCG vaccine have been tried with

marginal and unpredictable results.• Drug therapy (dacarbazine), therapeutic radiation, and

immunotherapy are used in the treatment of cutaneous melanoma, but they are of questionable benefit to patients with oral melanoma. Dacarbazine is not effective in the treatment of oral melanoma; however, dacarbazine administration in conjunction with interleukin 2 may have therapeutic value.

Treatment of metastatic melanoma

Single-agentchemotherapy

Multi-drugcombinationNitrosourea +vinca alkaloids

+ platinumcompounds +dacarbazine

ImmunotherapiesINF-α, IL-2,

combination ofINF-α + IL-2

BiochemotherapyDacarbazine +

INF-α + IF-2

DacarbazineTemozolomide(DTIC analog)

NitrosoureasFotemustine

OthersCisplatin

CarboplatinVinblastineVindesine


Newer agents used for treating melanoma

Lenalidomide (a thalidomide derivative)Thalidomide + temozolomideTaxane ABI-007SorafenibAnti-Bcl-2 antisenseAnti-Bcl-2 antisense + dacarbazineMEDI-522 humanized monoclonal antibodyCytotoxic T-lymphocyte antigen-4 (CTLA-4)Ipilimumab with or without dacarbazine combination


PHYSIOLOGICAL PIGMENTATION

Due to greater melanocyte activity rather than a greater

number of melanocytes.

This type of pigmentation is symmetric and persistent and

does not alter normal archaistic such as gingival stippling

Blacks, Asians, dark skinned caucasians most frequently

show diffuse melanosis of facial gingiva

In addition, lingual gingiva & tongue may exhibit multiple

diffused and reticulated brown macule

Seen in patients at any age, no gender predilection

No further attention is required, in case of

doubt, it should be excised and sent

for histopathological study.

Lingual gingiva & tongue may exhibit multiple, diffuse &

reticulated brown macule

Basilar melanosis, evolves in childhood

Multifocal or diffuse pigmentation of recent onset –

investigated-endocrinopathic disease.

Does not alter normal architecture

Degree of intraoral pigmentation –may not correspond

cutaneous coloration

No change in intensity

SMOKER’S MELANOSIS

Diffuse macular melanosis of buccal mucosa, palate, lateral tongue, floor of the mouth is usually seen among the smokers

Tobacco smoke products stimulates the melanocytes and causes hyperpigmentetion. increased production of melanin, which may provide a biologic defence against the noxious agents present in tobacco smoke.

Clinically lesions are brown, flat & irregular some are geographic or map like in configuration

Intensity of pigmentation appears to be time and dose related Histologically basilar melanosis with melanin is observed

• Brown, flat, and irregular, geographic or

maplike

• basilar melanosis with melanin incontinence

• No premalignant potential

• Rx for Cosmetics

Drug induced MelanosisDrugs associated with oral mucosal pigmentation • Antimalarials: quinacrine, chloroquine, • hydroxychloroquine • Quinidine • Zidovudine (AZT) • Tetracycline • Minocycline • Chlorpromazine

ETIOLOGY

The pathogenesis of drug-induced pigmentation varies, depending on the causative drug. involve accumulation of melanin, deposits of the drug or one of its metabolites, synthesis of pigments under the influence of the drug or deposition of iron after damage to the dermal vessels.

• Quinidine: Mucosal discolouration is described as blue–grey or blue–black in most cases only the hard palate is involved

Blue grey pigmentation of the gingiva from Minocycline

Oral contraceptives &pregnancy are associated with hyperpigmentation of facial skin- periorbital & perioral region -melasma or chloasma.

Flat lesions, nail bed & skin

ENDOCRINOPATHIC PIGMENTATION

Bronzing of skin and patchy melanosis of the oral mucosa are signs of Addison’s Disease and Cushing’s Syndrome

Cause-hyperpigmentation is the oversynthesis of a ACTH hormone with melanocyte stimulating properties

In both, the skin may appear tanned and buccal mucosa may be blotchy.

The changes are due to accumulation of melanin granules

Serum steroid and ACTH will aid in diagnosis.

Addison’s disease

Granulomatous infection of cortex/ autoimmune cortical destruction

Adrenocortical insufficiency

Steroid hormones decrease Feedback loop stimulated

Excess secretion of ACTHHypotension and hypoglycemia,stimulation of MSH

ADDISON’S DISEASE

PEUTZ JEGHER’S SYNDROME

Autosomal dominant condition associated with intestinal

polyposis and pigmentation of oral mucosa, lips, skin.

Pigmentation is distinctive with lesions on anterior part of

tongue, buccal mucosa

Lesions are focal, multiple, melanotic brown macules less

than 0.5cm in diameter

Peutz-Jeghers

• Characterized by hyperpigmented macules on the lips and oral mucosa and polyposis of the small intestine

• Dark brown or black macules appear typically on the lips, especially the lower lip, in infancy or childhood

• Similar lesions may appear on buccal mucosa, tongue, gingiva, and genital mucosa

• Macules may also occur around the mouth, on the central face, backs of the hands, especially the fingers, and on the toes and tops of the feet.

• Associated polyposis involves the small intestine preferentially.

• But, hamartomatous polyps of the stomach and colon may occur.

• Symptoms of hamartomas of the small intestine may cause repeated bouts of abdominal pain and vomiting, and intussusception

Peutz-Jeghers Syndrome

• Cosmetic Rx of labial macules has been accomplished with the use of a 694-mm ruby laser

• incidence of malignancy within the polyps is 2-3%

• Incidence of GI malignancy is low, but increased incidence of other kinds of cancer-breast, and gynecologic malignancies in women

• Syndrome is inherited and transmitted as a simple mendelian dominant trait

• Sporadic noninherited cases may occur

• The gene (STK11/LKB1) has been localized to 19p13.3

• 19p13.3 is believed to be a tumor suppressor gene

Peutz-Jeghers Syndrome

• Cronkhite-Canada syndrome should be considered in DDx

• Characterized by melanotic macules on the fingers and gastrointestinal polyposis

• Also generalized , uniform darkening of the skin, extensive alopecia, and onychodystrophy

• The polys that occur are usually benign adenomas and may involve the whole GI tract

• A protein-losing enteropathy may develop and is associated with the degree of intestinal polyposis

• Onset is after age 30 yrs• Sporadically occurring,

benign condition• Hypogeusia is the

dominant initial symptom• Diarrhea and ectodermal

changes may follow• 75% of cases have been

reported in Japan

Peutz-Jeghers syndrome

• Lip lentigenes in an adolescent with Peutz-Jeghers syndrome

P-J syndrome

Histologically- lesions show basilar

melanosis without melanocytic proliferation

Café au Lait Pigmentation• Color of coffee with cream• Small ephelis-like macules to broad diffuse• Late childhood and multiple• Neurofibromatosis- nodular and diffuse

pendulous neurofibromas - skin and (rarely) in the oral cavity

• Basilar melanosis without melanocyte proliferation

• McCune Albright syndrome

DISEASES COMMONLY ASSOCIATED WITH CAFÉ AU LAIT PIGMENTATION

Ataxia-telangiectasia Neurofibromatosis type 1, Noonan’s syndrome

Familial café au lait spots Neurofibromatosis type 2

Familial cavernous malformation Nijmegen breakage syndrome

Fanconi’s anemia Noonan’s syndrome

Hereditary nonpolyposis colorectal cancer

Ring chromosome 7 syndrome

Idiopathic epilepsy Ring chromosome 15 syndrome

Johanson-Blizzard syndrome Ring chromosome 17 syndrome

McCune-Albright syndrome Russell-Silver syndrome

Microcephalic osteodysplastic primordial dwarfism

Tuberous sclerosis

Neurofibromatosis type 1 Turcot’s syndrome

ALBRIGHT’S SYNDROME/CAFE AU LAIT PIGMENTATION

Polyostotic fibrous dysplasia of bone is of two types

i) Albright’s Syndrome

- Fibrous dysplasia

- Café au lait spots

- Endocrinal disturbances

ii) Fibrous Dysplasia with CAFE AU LAIT spots

(Jaffe’s spots)

- irregular, pigmented melanotic spots varies from small macule to broad diffuse lesions

- light brown in color and occur rarely in oral cavity

• Microscopically Café au lait spots represents with basilar melanosis without melanotic proliferation

NEUROFIBROMATOSIS

• Individuals with 6 or more large (>1.5 cm in diameter) café-au-lait macules should be suspected of possibly having neurofibromatosis.

• 2 forms- NF1 (von recklinghausen’s disease), NF2 (acoustic neurofibromatosis).

• Axillary freckling (Crowe’s sign) accompanied by p/o 6 or more macules is pathognomonic for NF 1.

Pigmented Lichen Planus

• Erosive lichen planus + diffuse melanosis• Increased production of melanin by the

melanocytes • Accumulation of melanin laden macrophages

in the superficial connective tissue

PIGMENTED BASAL CELL CARCINOMA

Papular border

may have central ulceration.

Usually solar exposed surface in older patients

Patients usually has dark brown eyes and dark

brown or black hair.

NEUROECTODERMAL TUMOUR OF INFANCY

Benign neoplasm composed of premature pigment producing cells which have their origin in neural crest

Infants under 6 years of age

Occurs mainly in maxilla

Lesions present as non-ulcerated darkly pigment mass

TREATMENT—Surgical Excision

Laugier-Hunziker Pigmentation

• Acquired, idiopathic, macular hyperpigmentation of the oral mucosal tissues specifically involving the lips and buccal mucosae.

• Up to 60% of affected patients also may have nail involvement, usually in the form of longitudinal melanotic streaks w/o incidence of dystrophic change.


• 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.


• Diagnosis of exclusion• The pigmentation may be esthetically

unpleasing, but it is otherwise innocuous.• Rx is not indicated but laser and cryotherapy

have been used with some success.

HAEMOGLOBIN

BLUE/RED/PURPLE LESIONS

• HAEMANGIOMA

Raised, nodular, sometimes flat, macular & diffuse particularly on the facial skin and are called as PORT WINE STAINS

Most commonly tongue and lip mucosa On tongue they are multinodular & bluish red in color May occur in childhood, adults or elderly persons Depending on the depth of vascular proliferation

within the oral sub mucosa, the color of lesion varies. - If close to overlying epithelium- Reddish Blue - If deeper in connective tissues - Deep Blue

Port wine stain involves facial skin is flat &magenta I colour.

Skull radiograph: vessel wall calcification yield bilamellar radiopaque tracks

“Tram line calcification”• Bubbly or honeycomb trabeculated appearance• Overlying cortex is expanded and thinned, but

complete cortical disruption and invasion into soft tissue are not present

Diascopy Intraluminal clots form- palpable and do not blanch

Sunburst appearance

• Calcified nodules/phleboliths- radiographically

evident

• 85% of childhood-onset hemangiomas

spontaneously regress after puberty

TREATMENT

• Conventional surgery, laser surgery, cryosurgery

• Sclerosing agents - 1% sodium tetradecyl sulfate (intralesional

injection)- .05 to 0.15 ml/cm3

• Absolute ethanol has also been used

• Cutaneous port-wine stains - subcutaneous tattooing or by

argon laser

• If larger feeder vessels are present, embolization using metal

coils may significantly reduce arterial blood flow.

DDx

• Mucocele & Ranula: soft & fluctuant• Aneurysm: pulse is detected

Histopathology

• Cavernous -large dilated vascular channels lined by endothelial cells without a muscular coat

• Cellular/capillary-endothelial proliferation, vascular lumina are very small

• Intramuscular –deep lesions

Sturge Weber syndrome

• Encephalotrigeminal angiomatosis• Port wine stain (nevus flammeus) –

leptomeninges of cerebral cortex• Mental retardation, hemiparesis, seizures• Ocular lesions• Calcification • d/d- angioosteohypertrophy syndromePort wine stain + varices + hypertrophy of bone

Hemangioma Vascular malformation

Description Abnormal endothelial cell proliferation

Abnormal blood vessel development

Elements Includes no. of capillaries Mix of artery, vein, capillaries (AV shunt)

Growth Rapid congenital, ceases puberty

Grows throughout

Boundaries Circumscribed; rarely affects bone

Poorly circumscribed

Thrill & bruit absent present

Involution Spontaneous Does not involute

Resection Easy Difficult, surgical haemorrhage

Recurrence Uncommon Common

Blue rubber bleb nevus syndrome

• Bean’s syndrome• Multiple small & large cavernous

hemangioma • Skin & GI tract + mouth• Childhood/young adulthood• Life threatening-blood loss-> anemia & Fe

deficiency

VARICESPathologic dilatation of veins or venules

Ventral tongue – most common site“caviar tongue”

Blue, red, purple elevations that course over the ventrolateral surface on the tongue with extension anteriorly

Painless and not subject to rupture and haemorrhage

Varix resembles hemangioma both clinically and histologically but differs only in age of onset and etiology

DDx for Bulbous Varicosity

• Hemangioma• Aneurysm• Mucocele• Ranula• Superficial nonkeratotic cyst

ANGIOSARCOMA

Malignant vascular neoplasm can arise any where in the body

Oral cavity extremely rare

If superficial - red / blue / purple

If deep – nodular tumour

Can arise from blood or lymph vessels

Prognosis is poor

Treated by radical excision

KAPOSI’S SARCOMA

Tumor of putative vascular originMost commonly on hard palate and facial gingivaOral tumours – red , blue , purpleSkin tumours – localize in dorsal aspect of feet and

great toe2 forms- elderly men (oral mucosa & skin of lower

extremities), children in equatorial africa (lymph nodes)– aggressive & lethal

In HIV seropositive patients, the oral lesions are flat red macules of variable size & irregular configuration and later increases in size to become nodular growth

HHV-8

KAPOSI SARCOMA + HIV • Oral lesions - posterior hard palate• Begin as flat red macules of variable size

and irregular configuration • Numerous isolated and coalescing plaques• Eventually- increase in size -> nodular

growths- entire palate, protruding below the plane of occlusion

• Facial gingiva

DDx- pyogenic granuloma, giant cell granuloma

Bacillary angiomatosis-bartonella henselae-rare in

oral mucosa

Early stage-no Rx; later-electrocautery/excision

Intralesional 1% vinblastine sulfate- less post

injection pain- multiple biweekly injections

Proliferating spindle cells with mild pleomorphism +

plump endothelial cells

extravasation of erythrocytes + hemosidrin

granules

HEREDITARY HEMORRHAGIC TELANGIECTASIARendu-Osler-Weber syndrome

Multiple round or oval purple papules measuring less

than 0.5cm in diameter

Genetically transmitted disease

Over a hundred such purple papules on vermillion or

mucosal surface of lips, tongue & buccal mucosa

• Same lesion in nasal mucosa-epistaxis• differential diagnosis-petechial

hemorrhages (platelet disorder)-macular, red/blue, not genetic

• CREST syndromeTREATMENT :• Selective embolization• electrocautery (series of procedures) using local anesthesia

HEMOSIDERIN

BROWN HEME ASSOCIATED LESIONS

ECCHYMOSIS

Traumatic ecchymosis – most commonly on the lips and face

Immediately after the trauma, erythrocytes extravasates into the submucosa

Clinically appear bright red macule or swelling if a hematoma forms

The lesion then assume a brown discoloration within few days after haemoglobin is degraded to hemosiderin

TREATMENT :

Observation for 2 weeks

PETECHIAE

Capillary hemorrhages will appear red

initially, turning brown in few days once the

extravasated red cells have lysed and

degraded to hemosiderin

DDx for petechiae and ecchymosis

• Solitary- H/O trauma, change color from bluish-brown to green to yellow and then finally diassapear within 4-5 days.

• Do not blanch on pressure (as compared to telangiectasias)

• Multiple: – Trauma from fellatio– Trauma from severe coughing– Trauma from severe vomiting– Prodromal sign of infectious mononucleosis– Prodromal sign of hemostatic disease

HAEMOCHROMATOSIS

Disorder in which excess iron is deposited into the body and results in eventual sclerosis and dysfunction of the tissues/organs involved

Iron is then stored as HEMOSIDERIN AND FERRITIN

Cause of pigmentation is haemochromatosis i.e. an increase in melanin production and not the deposition of hemosiderin in the skin

This is due to increase in ACTH

Oral mucosal lesions - Brown to Grey, diffuse macules

Usually seen on palate and gingiva

HISTOPATHOLOGICALLY (lower labial gland Bx)- Basilar melanosis

DIAGNOSIS – Biopsy – stained with PRUSSIAN BLUE

– Iron levels elevated in serum

Also called as BRONZE DIABETES

JAUNDICE

OCCUR DUE TO LIVER DISORDERS

CAUSES IMPROPER METABOLISM OF

BILE PIGMENTS ASSOCIATED WITH

DEPOSITION OF BILE PIGMENTS IN SKIN

AND ORAL MUCOUS MEMBRANE

CAROTENECAROTENEMIA

Chronic excessive level of carotene pigments in the

tissues

Long and continued consumption of large amounts of

food like carrots, egg yolk

Disturbance in metabolism of these food to produce

Vitamin A may also increase carotene level

Orange yellow pigmentation of mucosa

No treatment is required other that dietary

modifications

LIPOFUSCIN

IT IS AN AGING PIGMENT WHICH WILL RARELY AFFECT THE ORAL MUCOSA

EXOGENOUS PIGMENTATIONGREY / BLACK / GREEN

IMPREGNATION OF FOREIGN SUBSTANCES

ACCIDENTAL IMPREGNATION

IATROGENIC IMPREGNATION

INCREASED EXOGENOUS PIGMENTATION

ACCIDENTAL IMPREGNATION

In road accident small bits of stone, gravel and send

get impregnated in the oral tissues, they, if removed

completely cause discoloration

Charcoal containing dentrifrices also produce black,

permanent discoloration due to constant use

IATROGENIC IMPREGNATION

AMALGAM TATTOO

Small pieces of amalgam can break off, impregnate into

gingival and oral tissues during fabrication and removal of

restoration or extrication of teeth

The lesions are macular and blushing gray of even black and

Usually seen in gingival and basement membrane and palate

Found in the vicinity of teeth with large amalgam rest or

crowned teeth

D/D- nevus , early melanoma

AMALGAM TATTOO

Microscopically, particles are typically aligned along collagen

fibres and around blood vessels

GRAPHITE TATTOOOccurs on the palate one to treatment implantation

of lead pencil

Lesions are macular, focal gray or black

Microscopically resembles amalgam.

INCREASED EXOGENOUS POISONING

Heavy metal poisoning – Arsenic, bismuth, lead &

mercury

Heavy metal and its excess leading to oral

manifestations is seen as most commonly in the

occupational hazards

INCREASED EXOGENOUS POISONING

Ingested pigments tend to extravasate from vessels in

foci of increased capillary permeability such as inflamed

tissues.

Free marginal gingiva-gingival cuff, resembling eyeliner-

gray-black app

Behavioral changes, neurologic disorders, and intestinal

pain.

MERCURALISMPINK DISEASE/ SWIFT DISEASE/ ACRODYNIA Potential occupational hazards for dentists and dental team mostly

arising from improper use of amalgam alloy

MECHANISM OF ACTION Short chain alkyl and methyl mercury penetrate the erythrocyte

membrane and bind to hemoglobin ORAL MANIFESTATIONS Flow of ropy viscid saliva Hot mouth, burning sensation, metallic taste Diffuse greyish pigmentation in the form of a line/band along the

alveolar mucosa Color: diffuse grayish pigmentation of alveolar mucosa, gums are

deeper hue than normal, teeth may exfoliate due to marked periostitis.

SYSTEMIC FINDINDS Diarrhoea, headache, insomnia, depression, Renal symptoms,

Tremors

TREATMENT Systemic- Bed rest, Diet control Oral – Atropine & Belladona to lessen the salivary flow Administration of BAL (British anti-lewisite)& dimercaprol

LEAD POISONING (PLUMBISM)

Caused by lead from exhausts, paints glazed cooking vessels,

ointments, batteries.

Irrespective of the absorption pathways (Elementary tract or

lungs), lead is taken up by circulating erythrocytes and bound

to reactive sulfhydryl group of proteins and transmitted to soft

tissues

In red cells inhibit enzymes associated with haemoglobin

synthesis

- Metallic taste, excessive salivation and dysphasia are

oral symptoms

A lead line (grey black) is present along gingival margin

BISMUTH POISONING

Medicinal use of bismuth in treatment of syphilis

A blue black bismuth line along gingival margin without symptoms

Metallic taste with burning sensation

Tongue is frequently sore and enlarged

Maintain oral hygiene

ARSENIC POISONING

Industrial exposure, accidental or intentional poisoning

Oral lesions are externally painful and are deep red in color

Chronic gastritis and collitis are frequently the only symptoms

with occasional keratosis

Arsine gas combines with globin chain of haemoglobin in

RBCs to produce severe anemia, haemoglobinuria and

hematuria with in 3-4 hours of ingestion.

ARGYRIA

Permanent discoloration of skin and mucous membrane

resulting from local or systemic absorption of silver

components

Bluish grey pigmentation is seen

Skin is slate grey, violet

or cyanotic

ARGYRIA

FOCAL ARGYROSIS

ZINC STOMATITISCongestion and suppuration of gingiva tissues

Bluish grey line

Metallic taste

SELF INFLICTED WOUNDS WITH COLORED PENCILS

The prognostic evaluation of the tattooing is based on the chemical composition, solubility and quantity of the coloring material

The acid base color materials usually present in colored pencils (e.g. methyl blue, methyl violet & others) are water soluble and used in food manufacture (e.g. ink stamps for meat).

They tend, because of their water solubility, to expand rapidly but also resorb and disappear rapidly.

RITUAL, DELIBERATE TATTOOING

Today, as in the past, decorative tattooing with paint, soot,& metallic pigments is in fashion with youths of certain population groups.On the oral mucosa these findings are rareIn young Africans groups, there are also certain ritual tattoos of the gingiva.They are considered as Beauty marks.For this purpose, soot obtained from burned wool soaked in oil into oral mucosa using needles bundles. The soot particles introduced in this manner create a lasting darkening of the gingiva which fades only after many years

MISCELLANEOUS

HAIRY TONGUE

Involves dorsum,especially middle and posterior one third of

the tongue

Papillae are elongated which becomes pigmented

1) Colonization of chromogenic bacteria that imparts a variety

of colors ranging from green,brown,black

2) Various foods – Coffee, Tea

TREATMENT :

Patient is advised to brush the tongue and keep it clean.

NEVI OF OTA Originally described by OTA and TANINO in 1939 Hematoma of dermal melanocytes Clinically blue or grey speckled coalesced macules

or patches on the face May be congenital or acquired Occurs within the distribution of ophthalmic or

maxillary branches of trigeminal nerve Usually unilateral but sometimes bilateral May involve ocular or oral mucosal surfaces

Most frequently in Asian population

with estimated prevalence of 0.2 – 0.6% in Japanese

Sex : Male : female 1 : 4.8

Age :

- First peak of onset occurs in infancy with as many as

50% of nevus of ota cases at birth or shortly after

- Second peak of onset during adolescent

- Cases have been reported in older patients also

• HISTOPATHOLOGY

Increased dermal melanocytes with surrounding fibrosis and

melanophages

DEPIGMENTATION

VITILIGO

• Vitiligo is a relatively common, acquired, autoimmune disease that is associated with hypomelanosis due to destruction of melanocytes.

• Pathogenesis is multifactorial –genetic and environmental.

• There maybe a single nucleotide polymorphism in a vitiligo-susceptibility gene that is also associated with susceptibility to other autoimmune diseases, including diabetes type 1, systemic lupus erythematous, and rheumatoid arthritis.

• Variable clinical presentation.• Focal areas of depigmentation or entire segment on

one side of the body maybe involved. Occasionally, vitiligo universalis.

• Vitiligenous lesions often present as well-circumscribed, round, oval or elongated, pale or white-colored macules that may coalesce into larger areas of diffuse depigmentation.

• Any age, before 3rd decade usually.• No sex predilection.• May also arise in patients undergoing

immunotherapy for malignant melanoma.

• Rarely affects the intraoral mucosal tissues.

• However, hypomelanosis of the inner and outer surfaces of the lips and perioral skin maybe seen in upto 20% of patients.

• A case of perioral leukoderma simulating vitiligo developed in a 25-year-old woman. A patch test to cinnamic aldehyde (present in a toothpaste which the patient was using) was positive; depigmentation was observed at the patch test site three months after initial application.

Mathias CG, Maibach HI, Conant MA. Perioral leukoderma simulating vitiligo from use of a toothpaste containing cinnamic aldehyde. Arch Dermatol. 1980 Oct;116(10):1172-3.

• Microscopically, there is complete l/o melanocytes and melanin pigmentation in basal cell layer.

• Fontana Masson stain will confirm a/o melanin.

NORMAL VITILIGO

MANAGEMENT

• Topical corticosteroids• Topical/systemic photochemotherapies

(PUVA)• Medicinal depigmentation- cutaneous

bleaching for unified skin color.• Labial vitiligo is more resistant to Rx.• Surgical- autologous epithelial grafts,

punch grafting, micropigmentation.

WORKUP

Differential Diagnosis of Oral Pigmented Lesion

1 .Full medical and dental history, the history should include the onset and duration of the lesion, the presence of associated skin hyperpigmentation the presence of systemic signs and symptoms ( e.g malaise, fatigue, weight loss) and smoking habits.

2 .Extra oral and intra oral examinations. Pigmented lesions on the face, perioral skin and lip should be noted. The number, distribution, size, shape and colour of intraoral pigmented lesions should be assessed.

3 .Investigations such as diascopy test, radiography, biopsy and laboratory investigations such as blood test can be used to confirm a clinical impression and reach a definitive diagnosis.

HISTORY

RACIAL/PHYSIOLOGIC PIGMENTATION

NON-PHYSIOLOGIC PIGMENTATION

HISTORY OF SMOKING, TOBACCO USE, PAAN CHEWING, SMOKER’S

MELANOSIS

H/O OF FILLINGS(AMALGAM TATTOO)

NO ATTRIBUTABLE FACTORS OR PATHOLOGY

MEDICAL HISTORY



MEDICAL HISTORY

Positive forInflammatory conditions (LP)Bleeding historyVascular lesionsEndocrine disorders History of intestinal polyposisOther syndromes (Laungier-Hunziker, McCune-Albright,PTEN hamartoma tumor)HIV Metal ingestion/toxicity History of drug ingestion

If negative, consider

BenignpigmentationsMelanotic neviMelanoacanthomaMelanotic macules

Malignantmelanoma

Diagnosis justified on history

If yes, treataccordingly

If no, biopsy

If benign,treat if necessary

If malignant,treat immediately

Follow-up

Laboratory Studies

• In Peutz-Jeghers syndrome, a complete blood cell count should be obtained because the polyps may be a source of blood loss.

• For amalgam tattoos, a periapical radiograph reveals the presence of the amalgam.

• The only study effective for diagnosing oral malignant melanoma is tissue biopsy. A biopsy should be performed on any otherwise unexplained lesions.

• To avoid iatrogenic pigmentations, eliminate the causes (eg, smoking, sun exposure).

Imaging Studies

• Peutz-Jeghers syndrome: An enteroclysis study and dedicated small bowel follow-through radiography are used to determine the presence and the location of small intestinal polyps.

• Amalgam tattoos: These lesions can be seen on radiographs, which quickly verify the histologic findings.

• Iatrogenic pigmented lesions do not require any laboratory tests except photographs for documentation.

Nevi and melanoma • Imaging studies are not required for oral nevi, with the exception of

clinical photographs for documentation. However, contrast-enhanced CT scanning is required to determine the extent of the melanoma and whether local, regional, or lymph node metastasis is present.

• Studies such as bone scanning with a gadolinium-based agent or chest radiography can be beneficial in assessing metastasis of melanoma.

• MRI may be used to diagnose melanoma in soft tissue. Atypical intensity is correlated with the amount of intracytoplasmic melanin. On T1-weighted images, such melanomas are hypointense. On T2-weighted images, such melanomas are hyperintense and show increased melanin production. To the authors' knowledge, oral melanomas have not been assessed in this manner.

• Positron emission tomography has poor results in distinguishing melanoma from nevi. However, combined positron emission tomography and CT scanning may have diagnostic value. Surgical lymph node harvesting depends on the identification of positive nodes after clinical or imaging examination.

Other Tests

• Periapical radiographs are helpful to verify the presence of an amalgam tattoo.

Procedures• Peutz-Jeghers syndrome An esophagogastroduodenoscopy and a

colonoscopy may be performed.• Hemorrhagic or large polyps (>5 mm) should be removed by endoscopic

polypectomy to confirm the diagnosis and to help control symptoms. • Laparotomy and resection should be performed for repeated or

persistent small intestinal intussusception or obstruction or for persistent intestinal bleeding.

• MelanomaA pigmented lesion in the oral cavity always suggests oral malignant melanoma. Any pigmented lesion of the oral cavity for which no direct cause can be found requires biopsy.

• Sentinel node biopsy or lymphoscintigraphy, which is beneficial in the staging of cutaneous melanoma, has little value in staging or treating oral melanoma. Complex drainage patterns may result in the bypass of some first-order nodes and in the occurrence of metastasis in contralateral nodes.

http://emedicine.medscape.com/article/1819350-overview

Histologic Findings• The characteristic pathologic finding of the pigmentation seen in

the Peutz-Jeghers syndrome is basilar hyperpigmentation.• Although any of the features of cutaneous malignancy can be

found, most oral melanomas have characteristics of the acral lentiginous (mucosal lentiginous) and, occasionally, superficial spreading types. The malignant cells often nest or cluster in groups in an organoid fashion; however, single cells can predominate. The melanoma cells may have large nuclei, often with prominent nucleoli, and they have nuclear pseudoinclusions due to irregularity of the nuclear membrane. The abundant cytoplasm may be uniformly eosinophilic or optically clear. Occasionally, the cells become spindled or neurotize in areas.

• Melanomas have a number of histopathologic mimics, including poorly differentiated carcinomas and anaplastic large cell lymphomas. Differentiation requires the use of immunohistochemical techniques to highlight intermediate filaments or antigens specific for a particular cell line. Leukocyte common antigen and Ki-1 are used to identify the lymphocytic lesions. Cytokeratin markers, often cocktails of high- and low-molecular – weight cytokeratins, can be used to help in the identification of epithelial malignancies.

• S-100 protein and homatropine methylbromide (HMB-45) antigen positivity are characteristic of, although not specific for, melanoma. S-100 protein is frequently used to highlight the spindled, more neural-appearing melanocytes, whereas HMB-45 is used to identify the round cells. Melanomas, unlike epithelial lesions, are identified using vimentin, a marker of mesenchymal cells.

• Recently, microphthalmic transcription factor, tyrosinase, and melano-A immunostains have been used to highlight melanocytes. The inclusion of these stains in a panel of stains for melanoma may be beneficial.

• Various types of lasers have been used, including superpulsed CO2, Q-switched Nd-YAG, and Q-switched alexandrite lasers.

• Although laser and cryotherapy have been used to successfully treat such cases, experimental forms of phototherapy have also been employed, including intense pulsed light and fractional photothermolysis.

• First-line therapy remains the application of topical medicaments that is bleaching creams.

• Although single agents such as azelaic acid or hydroquinone have been used, more commonly dual- or triple-combination therapy is recommended.

• A combination of 4% hydroquinone- 0.05% retinoic acid- 0.01% fluocinolone acetonide has proven to be effective in greater than 90% of patients.

FOLLOW-UP• Peutz-Jeghers syndrome: Close follow-up care is needed for the GI aspects of the

disease. Genetic counseling should be offered to families trying to have children. Further outpatient care for patients with Peutz-Jeghers syndrome includes the following: Annual physical examination that includes evaluation of the breasts, the abdomen, the pelvis, and the testes

• Annual complete blood cell count• Repeated removal of hemorrhagic or large polyps (>5 mm) by endoscopic

polypectomy• Surveillance for cancer, possibly including the following:

– Small intestine with small bowel radiography every 2 years– Esophagogastroduodenoscopy and colonoscopy every 2 years– Ultrasonography of the pancreas yearly– Ultrasonography of the pelvis (women) and testes (men) yearly– Mammography (women) at ages 25, 30, 35, and 38 years; every 2 years until age 50 years;

then annually– Papanicolaou (Pap) test every 3 years

http://emedicine.medscape.com/article/1819350-overview

• Amalgam tattoos: No follow-up care is necessary for amalgam tattoos once the diagnosis is determined.

• Melanoma Patients with melanoma must receive close follow-up care involving oncologists, surgical oncologists, radiologists, and dermatologists.

• In many instances, psychological assistance and intervention is also necessary.

COMPLICATIONS

Peutz-Jeghers syndrome • In young patients, small intestinal obstruction and

intussusception are the main complications. • Cancer is the main consequence as patients with Peutz-

Jeghers syndrome age (93% cumulative risk by age 64 y). The major sites are the small intestine, the stomach, the pancreas, the colon, the esophagus, the ovaries, the lungs, the uterus, and the breasts.

• In addition, other reproductive site cancers have been associated with Peutz-Jeghers syndrome, including adenoma malignum of the cervix, Sertoli cell tumors, and sex cord tumors with annular tubules.

• Amalgam tattoos: No major complications are reported.

• Melanoma complications stem from the loss of anatomic structures as a result of the surgical procedure.

• Interferon use is associated with malaise, flulike symptoms, fever, and myalgia.

PROGNOSIS

• Peutz-Jeghers syndrome: Approximately 48% of patients with Peutz-Jeghers syndrome develop and die from cancer by age 57 years.

• Amalgam tattoos: The prognosis for patients with amalgam tattoos is excellent because the condition is not associated with any sequelae.

• Melanoma: 5-year survival rate is within a broad range of 4.5-48%

PATIENT EDUCATION

• Patients with Peutz-Jeghers syndrome should be educated on the potential symptoms of intestinal obstruction and instructed on the need for cancer surveillance.

• Reassurance is all that is necessary for patients with amalgam tattoos.

• Patients with melanoma should learn how to perform an effective oral examination.

REFERENCES• Burket’s Oral Medicine 11th Ed• Differential Diagnosis of Oral and Maxillofacial lesions 5th Ed Wood Goaz• Oral pthology 4th Ed Regezi Sciubba Jordan• Textbook of Oral Medicine 2nd Ed Anil Govindrao Ghom• Fundamentals of Oral Medicine and Radiology, Bailoor Nagesh• Adel Kauzman, Marisa Pavone, Nick Blanas. Pigmented Lesions of the Oral

Cavity: Review, Differential Diagnosis, and Case Presentations. Journal of the Canadian Dental Association. November 2004, Vol. 70, No. 10

• Pai A, Prasad S, Patil BA, Dyasanoor S, Hegde S. Orla pigmentation: Case report and review of malignant melanoma with flow charts for diagnosis and treatment. General Dentistry. 2012; 410-416.

• Gondivkar SM, Indurkar A, Degwekar S, Bhowate R. Primary oral malignant melanoma- A case report and review of literature. Quitessence International. 2009; 40(1): 41-46.

• Mathias CG, Maibach HI, Conant MA. Perioral leukoderma simulating vitiligo from use of a toothpaste containing cinnamic aldehyde. Arch Dermatol. 1980 Oct;116(10):1172-3.

• Medscape

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Health & Medicine

Oral Pigmentation