Oral Pigmentation

1. O R A L PI GM EN TA TI ON

2. INTRODUCTION CLASSIFICATION ENDOGENOUS PIGMENTATION EXOGENOUS PIGMENTATION DRUG RELATED PIGMENTED LESIONS ASSOCIATED SYNDROMES MISCELLANEOUS - HIV INFECTIONS - NEVI OF OTA DEPIGMENTATION WORKUP INDEX

3. PIGMENT C o l o r or Coloring Agent NORMAL MUCOSA Pale pink to deep bluish purple sometimes even blackish

4. NORMAL RANGE DEPENDS UPON Melanogenesis and distribution of melanin pigment Keratinization Depth of epithelization Vascularity

5. 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

6. FACTORS AFFECTING MELANOGENESIS Increased sun exposure Drugs Hormones Genetic constitution

7. Overproduction Over population Sun exposure , drugs, hormones Benign nevi, malignant melanoma

8. CLASSIFICATION 1. ENDOGENOUS PIGMENTATION 2. EXOGENOUS PIGMENTATION 3. DRUG RELATED PIGMENTED LESIONS 4. ASSOCIATED SYNDROMES 5. MISCELLANEOUS - HIV INFECTIONS - NEVI OF OTA

9. 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

10. 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, DRUGS MERCURY CHROMOGENIC BLACK/ SUPERFICIAL COLONIZATION BACTERIA BROWN/ GREEN

11. PIGMENTED LESIONS Diffuse & bilateral Focal Early onset Adult onset Non blanching No systemic S ystemic Blanching Red-blue-purple Blue-grey Brown - Physio logic - Peutz - Jeghers synd Addisons disease Heavy metal Kaposi’s sarcoma Drug induced Post infl ammatory Smokers melanosis Melanotic macule Pigmented nevus Melanoma Melano acanthoma Thrombus Hematoma Amalgam Tattoo 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

12. 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

13. 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’S GREY/ AMALGAM AMALGAM HEAVY METAL BLACK GRAPHITE HAIRY TONGUE INGESTION NEVUS MELANOMA

14. 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

15. 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.

16. EPHELIS (EPHELIDES/FRECKLES )

17. 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

18. 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

19. 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

20. 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.

21. 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

22. Melanocytes form clusters at the epitheliomesenchymal junction proliferate down into the connective tissue Dome shaped appearance Compound nevi Lose their continuity with surface epithelium+ cells become localized - deeper connective tissues Intradermal nevi (skin) Intramucosal (mouth)

23. INTRADERMAL NEVI COMPOUND NEVI JUNCTIONAL NEVI

24. INTRAMUCOSAL NEVUS- appears as brown and black elevated papules

25. 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.

26. 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.

27. COMPOUND NEVUS

28. 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.

29. INTRAMUCOSAL NEVUS

30. JUNCTIONAL NEVUS

31. COMPOUND NEVUS

32. BLUE NEVUS

33. 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

34. TYPES Superficial spreading melanoma Nodular melanoma Lentigo maligna melanoma Acral lentiginous melanoma Mucosal lentiginous melanoma Amelanotic melanoma

35. 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

36. 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

37. SUSPICIOUS CHANGES IN NEVI 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.

38. “ 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 prognosis Nodular-deeper invasion-vertical growth-poor

39. 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

40. 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

41. 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.

42. Tumor Depth Approximate 5 year survival <1 mm 95-100% 1 - 2 mm 80-96% 2.1 - 4 mm 60-75% >4 mm 50%

43. DDx CONDITION 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

44. TREATMENT Excision with wide margins CT & MRI-Rule our metastases- submandibular & cervical nodes Immunosuppressive drugs

45. Treatment protocol for malignant melanoma Surgery Surgery and combined therapy Others Cancer/testis antigens (CTAs) expression profile for vaccine development Gene therapy OK432 (a biologic response modifier) Radiotherapy Chemotherapy Immunotherapy Curative chemotherapy Dimethyl triazeno imidazole carboxamide (DTIC) Nimustine hydrochloride (ACNU) Vincristine (VNC) Palliative chemotherapy Dacarbazine Platinum analogs Nitrosoureas Microtubular 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.

46. 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.

47. Treatment of metastatic melanoma Single-agent chemotherapy Multi-drug combination Nitrosourea + vinca alkaloids + platinum compounds + dacarbazine Immunotherapies INF- α, IL-2, combination of INF- α + IL-2 Biochemotherapy Dacarbazine + INF- α + IF-2 Dacarbazine Temozolomide (DTIC analog) Nitrosoureas Fotemustine Others Cisplatin Carboplatin Vinblastine Vindesine 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.

48. Newer agents used for treating melanoma Lenalidomide (a thalidomide derivative) Thalidomide + temozolomide Taxane ABI-007 Sorafenib Anti-Bcl-2 antisense Anti-Bcl-2 antisense + dacarbazine MEDI-522 humanized monoclonal antibody Cytotoxic 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.

49. 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

50. 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

51. 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

52. Brown, flat, and irregular, geographic or maplike basilar melanosis with melanin incontinence No premalignant potential Rx for Cosmetics

53. Drug induced Melanosis Drugs 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

54. Blue grey pigmentation of the gingiva from Minocycline

55. Oral contraceptives &pregnancy are associated with hyperpigmentation of facial skin- periorbital & perioral region - melasma or chloasma . Flat lesions, nail bed & skin

56. 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 ho rmone 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.

57. Addison’s disease Granulomatous infection of cortex/ autoimmune cortical destruction Adrenocortical insufficiency Steroid hormones decrease Feedback loop stimulated Excess secretion of ACTH Hypotension and hypoglycemia,stimulation of MSH

58. ADDISON’S DISEASE

59. 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

60. 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

61. 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

62. 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

63. Peutz-Jeghers syndrome Lip lentigenes in an adolescent with Peutz-Jeghers syndrome

64. P-J syndrome

65. Histologically - lesions show basilar melanosis without melanocytic proliferation

66. 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

67. 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

68. 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

69. 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.

70. 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

71. 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.

72. 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

73. 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.

74. 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.

75. 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.

76. HAEMOGLOBIN BLUE / RED / PURPLE LESIONS

77. 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

78. 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

79. Sunburst appearance

80. Calcified nodules/ phleboliths - radiographically evident 85% of childhood-onset hemangiomas spontaneously regress after puberty

81. 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.

82. DDx Mucocele & Ranula : soft & fluctuant Aneurysm: pulse is detected

83. 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

84. Sturge Weber syndrome Encephalotrigeminal angiomatosis Port wine stain (nevus flammeus ) – leptomeninges of cerebral cortex Mental retardation, hemiparesis , seizures Ocular lesions Calcification d/d- angioosteohypertrophy syndrome Port wine stain + varices + hypertrophy of bone

85. 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

86. 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

87. VARICES Pathologic 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

88. DDx for Bulbous Varicosity Hemangioma Aneurysm Mucocele Ranula Superficial nonkeratotic cyst

89. 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

90. KAPOSI’S SARCOMA Tumor of putative vascular origin Most commonly on hard palate and facial gingiva Oral tumours – red , blue , purple Skin tumours – localize in dorsal aspect of feet and great toe 2 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

91. 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

92. 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

93. HEREDITARY HEMORRHAGIC TELANGIECTASIA Rendu -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

94. Same lesion in nasal mucosa- epistaxis differential diagnosis- petechial hemorrhages (platelet disorder)-macular, red/blue, not genetic CREST syndrome TREATMENT : Selective embolization electrocautery (series of procedures) using local anesthesia

95. HEMOSIDERIN BROWN HEME ASSOCIATED LESIONS

96. 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

97. PETECHIAE Capillary hemorrhages will appear red initially, turning brown in few days once the extravasated red cells have lysed and degraded to hemosiderin

98. 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

99. 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

100. JAUNDICE OCCUR DUE TO LIVER DISORDERS CAUSES IMPROPER METABOLISM OF BILE PIGMENTS ASSOCIATED WITH DEPOSITION OF BILE PIGMENTS IN SKIN AND ORAL MUCOUS MEMBRANE

101. CAROTENE CAROTENEMIA 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

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

103. EXOGENOUS PIGMENTATION GREY / BLACK / GREEN IMPREGNATION OF FOREIGN SUBSTANCES ACCIDENTAL IMPREGNATION IATROGENIC IMPREGNATION INCREASED EXOGENOUS PIGMENTATION

104. 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

105. IATROGENIC IMPREGNATION

106. 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

107. AMALGAM TATTOO Microscopically, particles are typically aligned along collagen fibres and around blood vessels

108. GRAPHITE TATTOO Occurs on the palate one to treatment implantation of lead pencil Lesions are macular, focal gray or black Microscopically resembles amalgam.

109. 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

110. 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.

111. MERCURALISM PINK 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 .

112. 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

113. 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

114. 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

115. 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.

116. 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

117. ARGYRIA

118. FOCAL ARGYROSIS

119. ZINC STOMATITIS Congestion and suppuration of gingiva tissues Bluish grey line Metallic taste

120. 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 .

121. 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 rare In 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

122. MISCELLANEOUS

123. 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.

124. 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

125. 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

126. DEPIGMENTATION

127. 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.

128. 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 3 rd decade usually. No sex predilection. May also arise in patients undergoing immunotherapy for malignant melanoma.

129. 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.

130. 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.

131. Microscopically, there is complete l/o melanocytes and melanin pigmentation in basal cell layer. Fontana Masson stain will confirm a/o melanin. NORMAL VITILIGO

132. 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 .

133. WORKUP

134. 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 .

135. 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.

136. 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 for Inflammatory conditions (LP) Bleeding history Vascular lesions Endocrine disorders History of intestinal polyposis Other syndromes ( Laungier - Hunziker , McCune-Albright, PTEN hamartoma tumor) HIV Metal ingestion/toxicity History of drug ingestion If negative, consider Benign pigmentations Melanotic nevi Melanoacanthoma Melanotic macules Malignant melanoma Diagnosis justified on history If yes, treat accordingly If no, biopsy If benign, treat if necessary If malignant, treat immediately Follow-up

137. 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).

138. 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.

139. 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.

140. Other Tests Periapical radiographs are helpful to verify the presence of an amalgam tattoo.

141. 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.

142. 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.

143. 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.

144. Various types of lasers have been used, including superpulsed CO 2 , Q-switched Nd -YAG, and Q-switched alexandrite lasers.

145. 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 .

146. 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.

147. 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

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

149. 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.

150. 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.

151. 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 .

152. 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%

153. 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.

154. REFERENCES Burket’s Oral Medicine 11 th Ed Differential Diagnosis of Oral and Maxillofacial lesions 5 th Ed Wood Goaz Oral pthology 4 th Ed Regezi Sciubba Jordan Textbook of Oral Medicine 2 nd 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

155. T H A N K Y O U ! !