Oral Pigmentation
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Transcript of 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
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.
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
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.
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.
Laugier-Hunziker Pigmentation
• 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.
Laugier-Hunziker Pigmentation
• 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
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.
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.
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.
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
• 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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