Vol. 105 No. 5 May 2008

ORAL AND MAXILLOFACIAL PATHOLOGY Editor: Mark W. Lingen

Pigmented lesions of the oral mucosa and perioral tissues: aflow-chart for the diagnosis and some recommendationsfor the managementMarco Meleti, DDS,a,b Paolo Vescovi, DDS,a Wolter J. Mooi, MD, PhD,c andIsaäc van der Waal, DDS, PhD,b Parma, Italy and Amsterdam, The NetherlandsUNIVERSITY OF PARMA AND VRIJE UNIVERSITEIT MEDICAL CENTER/ACTA (ACADEMISCH CENTRUMTANDHEELKUNDE AMSTERDAM)

The term “pigmentation of the oral mucosa” is applied to a wide range of lesions or conditions featuring achange of color of oral tissues. Lesions not associated with an accumulation of pigment (e.g., Fordyce spots) areusually not classified as pigmented lesions. Two groups of pigmented lesions of the oral mucosa are recognized: 1)melanin-associated lesions, including racial pigmentations, melanotic macules, melanocytic nevi, and malignantmelanoma; and 2) nonmelanin-associated lesions (e.g., blood-related pigmentations, metallic pigmentations). Thispaper presents a clinicopathologic review of the recent literature with emphasis on the main diagnostic features,including the use of immunohistochemical markers. A flow-chart is added that may help the clinician in the diagnosis

and management of these lesions. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;105:606-16)

Human oral mucosa is not uniformly colored, and severaldegrees of chromatic variegation may be observed inphysiologic and pathologic conditions.1-5 Oral subsites arecharacterized by different structural colors, depending ondegree of keratinization, numbers and melanogenic activ-ity of melanocytes, vascularization, and type of submuco-sal tissue (muscle, bone, cartilage). The physiologic colorof the oral mucosa thus ranges from white to red-purple inlight-skinned people, whereas an evenly black to browncolor of gingiva and buccal mucosa and the lips arecharacteristic of dark-skinned people.1-5

In the present review, 2 groups of pigmented lesions arediscussed: melanotic lesions and lesions caused by otherpigments. After an overview of oral histology and phys-

aUnit of Oral Pathology and Medicine, Section of Odontostomatol-ogy, Department of ENT, Dental, Ophthalmological, and Cervicofa-cial Sciences, University of Parma.bDepartment of Oral and Maxillofacial Surgery/Oral Pathology, VrijeUniversiteit Medical Center/ACTA.cDepartment of Pathology, Vrije Universiteit Medical Center/ACTA.Received for publication Mar 19, 2007; returned for revision May 13;accepted for publication Jul 30, 2007.1079-2104/$ - see front matter© 2008 Mosby, Inc. All rights reserved.

doi:10.1016/j.tripleo.2007.07.047

606

iology of melanocytes, a flow-chart will be presented thatmay help the clinician in the diagnostic process (Fig. 1).

MELANIN-ASSOCIATED PIGMENTED LESIONSOF THE ORAL CAVITY

Oral mucosal melanocytes: histology andphysiology

Melanocytes were first identified in the oral epitheliumby Becker in 19276; a few years later they were isolatedfrom samples of gingival tissue by Laidlaw and Cahn.7

During early intrauterine life, precursors of melanocytes,melanoblasts, migrate from the neural crest to the epider-mis and the hair follicles, becoming differentiated den-dritic cells.8-10 The head and neck region represents thefirst part of the body where melanocytes appear, afterapproximately 10 weeks of gestation.10

Melanocytes are located in the basal epithelial layer ofsquamous mucous membranes and do not contact eachother. They are regularly interspersed between the basalkeratinocytes. Melanocytic dendrites reach a number ofkeratinocytes in the close vicinity, and through these den-drites melanin is transported and transmitted to theseepithelial cells.4,11-13 An age-related increase of oral me-lanocytes has been observed.14

The normal melanocytes of the oral mucosa have a

e cons

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small round nucleus and a small amount of a clear cyto-plasm, with slender dendrites extending between adjacentkeratinocytes. Melanocytes are devoid of desmosomes orattachment plates.15 Melanin-containing electron-densevesicles, so-called melanosomes, are formed within thecytoplasm and transported along the dendrites.13

The use of 3,4-dihydroxyphenylalanine, a substratefor tyrosinase, represents the most specific histochem-ical method for labeling melanocytes.11 Other methodsinclude argentaffinic melanin-labeling techniques suchas the Masson-Fontana staining. Inactive oral mucosalmelanocytes, lacking melanin and melanin precursors,may not stain with this method.11

Immunohistochemically, the S100 antigen is by farthe most common marker used. The S100 stainingappears to be stronger in melanocytes lacking pigment.Another commonly used marker is HMB-45, a mono-clonal antibody directed against a melanosomal glyco-protein.1,14 It is not expressed by melanocytes that lack

Pig

No or low clinical suspicion of

malignancy (ABCD, checklist, recent

history, age, subsite*)

Non-melano

Diagnosis justified on clinical grounds alone

(usually no treatment or follow-up required)**

(Medical) history allows to distinguishbetween melanocytic and non-melanocyt

lesions

Clinical suspicion of malignancy (ABCD

checklist, recent history, age,

subsite*)

Melanocytic lesion(s)

Fig. 1. Diagnosis and management of pigmented lesions.development. **In case of multiple or diffuse pigmentation(Addison disease, Peutz-Jeghers syndrome, and so on) may b

all melanogenic activity.11

The main biochemical function of the mature mela-nocyte is a process called melanogenesis, throughwhich the cell produces and delivers melanin pigment.9

Eumelanin (brown-black melanin) causes a brown-black color of the skin, hair, and eye, and pheomelaninhas a reddish color. Neuromelanin, found in some nervecells, is an unrelated substance.16

Various stimuli, such as trauma, hormonal changes,medication, and radiation, may result in an increasedproduction of melanin.17 Melanin functions include ab-sorption of ultraviolet light and scavenging of some cyto-toxic compounds.13

Racial pigmentation (physiologic pigmentation)No agreement exists in the literature on the definition of

“race,” “racial group,” “ethnic group,” or “ethnicity.”18

Furthermore, it has been demonstrated that the strength ofthe relationship between skin color and ancestry is quitevariable. As a matter of fact, the melanin content of the

sion of oral cavity and lips

(Medical) history does not allow to distinguish between melanocytic and non-

melanocytic lesions

iagnosis not possible on clinical grounds alone provisional diagnosis”)

on(s)

Biopsy or refer to a specialist for further

evaluation

Malignant melanoma

No malignancy (treatment usually not required,

nor follow-up)

te and gingiva are considered subsite at risk for OMMher examination for underlying diseases or syndromes (e.g.,idered.

mented le

D

(“

cytic lesi

ic

*Palas), furt

skin does not seem to be strictly related to ancestry,

OOOOE608 Meleti et al May 2008

genetically defined by the so-called “ancestry-informativemarkers.”18 On the basis of a multivariate evaluation, 3categories of humans have been defined: whites, blacks,and intermediates. Factors considered include skin colorin the medial part of the arm, color and texture of the hair,and shape of nose and lips.19

Oral “racial” pigmentations (ORPs) are usually ob-served in dark-skinned populations.1-5 In a study of1,300 children, ORPs were identified in 13.5%.17 Pig-mentations are usually diffuse and bilateral,although avariety of patterns have been observed.1,3 Color rangesfrom light dark to brown. Gingiva, with the exclusionof the marginal border, and buccal mucosa are the mostcommonly involved sites (Fig. 2). Other sites includelips, palate, and tongue1-5 (Fig. 3).

Racial pigmentations are innocuous, and treatment isonly for aesthetic reasons.

Melanotic maculesMelanotic macules of the oral cavity are relatively

common lesions, caused by an increased productionand deposition of melanin within the basal cell layer,the lamina propria, or both.1-3

In the largest series from 1 source, Buchner et al.reported that melanotic macules of the lips and oral cavityrepresented 86.1% (665 cases) in a group of 773 cases ofsolitary melanocytic lesions, which represented 0.7% of agroup of nearly 90,000 biopsies from oral cavity andperioral tissues.20 Of these, 207 were located on the lipsand 458 involved various subsites of the oral mucosa. Thevermilion border and the gingiva were the most com-monly affected subsites (60%). In another review, Kau-gars et al. reported a prevalence of 0.4% among 86,202biopsies from the oral cavity. Labial lesions almost exclu-sively affect the lower lip, whereas gingival melanoticmacules are more frequently localized in the anterior part

Fig. 2. Racial pigmentation. Gingival involvement.

of the maxilla. Black patients are more likely to have

involvement of the buccal mucosa.21 The female-to-maleratio is almost 2:1, and the highest incidence is reportedduring the fifth decade.20,21

Controversy exists on the pathogenetic mechanism thatleads to the development of melanotic macules, and it isnot clear if they represent a physiologic or a reactiveprocess.1 Some authors reported a positive family history,and a genetic predisposition has been hypothesized.22

Melanotic macules are usually single well circum-scribed blue or brown-to-black lesions homogeneouslycolored and less than 1 cm in diameter.1,3 Intraoral lesionstend to be larger than those located on the lips.1 Unlikeephelides, melanotic macules do not darken after exposureto sun radiation.23 Dermatoscopy may show a structure-less pattern, characterized by a diffuse brown-black pig-mentation, seldom irregularly distributed, without pig-ment network or globules and/or streaks.24 The diagnosisis usually made on clinical grounds alone.1

From the histopathologic point of view, there isabsence of rete ridge elongation and lack of promi-nent melanocytic activity.1-3 Pigmentation is usuallymost marked at the tips of the rete ridges, and mela-nophages can also be observed in the upper part oflamina propria.2,22 There is lack of atypia of mela-nocytes, and HMB-45 immunoreactyivity is typicallylacking.1,3,20,21,25 When melanin pigment is observedin the epithelium of a clinically nonpigmented lesion,the term “focal melanosis” has been used by some.26

Lentigines and ephelidesThe term lentigo (plural lentigines) indicates a well

defined hyperpigmented lesion of the skin with anincreased number of melanocytes arranged as solitaryunits along the epithelial-mesenchymal junction with-out formation of nests.27 Lentigines are subdivided intosimple lentigines and solar lentigines, the latter being

Fig. 3. Physiologic pigmentation on the tips of the fungiformpapillae.

associated with epithelial hyperplasia, which generally

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takes the form of rete ridge elongation. Melanocytichyperplasia is minimal in solar lentigines.

Lentigo simplex is a lesion histologically character-ized by more obvious melanocytic hyperplasia togetherwith increased melanin formation.27 No clear data onepidemiology are available in White populations,whereas lentigo simplex has been reported to be themost frequent pigmented lesion in acral sites of darklypigmented populations. Pathogenesis is most likely re-lated to developmental or intrinsic defects in melano-cytes homeostasis. Clinical features of lentigo simplexinclude light to dark brown pigmentation, usuallysharply circumscribed. Lesions can be single or multi-ple, the latter situation being associated with a numberof rare syndromes.27

Different from lentigo simplex, solar lentigines (syn-onyms sun-induced freckles, lentigo senilis) are ultra-violet light–induced pigmented lesions. Epidemiologyshows an increased incidence among the general pop-ulation over 60 years of age.1,3

Ephelides (freckles) are small (less than 1 cm) red orlight to dark brown macules localized on sun-exposedareas of the body.2,28 They typically affect light-skinnedindividuals, are multiple, and are uniform in color andregular in outline, although confluence leads to irregularlyshaped larger patches.2 Ephelides may appear at any agebut most frequently occur in childhood.2,28 They wax andwane with the degree of solar exposure, being most con-spicuous in the summer months.

No data exist on the prevalence of intraoral lentiginesand ephelides; they mainly affect the vermilion borderof the lips or the perioral tissues.2

Melanocytic neviOral melanocytic nevi (OMNs) are benign tumors of

melanocytes.27 Approximately 500 cases have beenreported in the English-language literature; no system-atically assembled data on their frequency are avail-able.20,29 A recent report from the Netherlands revealedan annual incidence of excised OMNs of 4.35 cases per10 million population per year.29

The etiology and pathogenesis of OMNs are poorlyunderstood even though, as for their cutaneous counter-part, oncogenic mutations of genes coding for componentsof the RAS signaling pathways may play a role.30

Regarding morphogenesis, the melanocytic prolifer-ation can be divided into 3 phases: 1) proliferation ofbenign neoplastic melanocytes along the epithelial-mesenchymal junction (junctional nevus); 2) migrationof these cells into the mesenchymal compartment (com-pound nevi); and 3) loss of the junctional component ofthe nevus, so that all remaining nevomelanocytes arelocated within the subepithelial compartment (subepi-

thelial nevi)12,27,31 (Fig. 4). These steps correspond to

the histologic variants of OMNs.29 Less common nevussubtypes include blue nevus (Figs. 5 and 6), combinednevus, and Spitz nevus.32-36

In the histopathologic evaluation, the additional use ofimmunohistochemical stains may be required, such as themelanocytic markers Melan A, HMB45, and microphthal-mia transcription factor. In melanin pigment–laden cells,additional markers, e.g. CD68, a marker for macrophages,may be helpful in identifying the nature of such cells.Such a procedure may be particularly helpful in arriving ata correct diagnosis of a blue nevus.

Congenital melanocytic nevi are present at birth,and those developing after birth are referred to asacquired nevi.37-39 Probably, most melanocytic neviof the oral mucosa are acquired,37 even though somecases of congenital nevi have been reported.38 Sizesrange from 0.1 to, rarely, 3.0 cm.37,40 The OMNstypically are well circumscribed round or oval mac-ules or papules, but polypoid larger lesions havebeen reported as well.27,37,40 The OMNs have beenreported to occur in a multiple fashion.41 Elevatedacquired nevi are usually lightly pigmented, whereasflatter lesions tend to be more darkly pigmented.27

Colors vary: brown to blue, bluish gray, or black;generally an individual lesion has a similar colorthroughout.27,37,40,42 Rare nonpigmented nevi are onrecord.43 The hard palate, buccal mucosa, and gin-giva are most commonly affected.37,40,42,44,45

Despite a strong epidemiologic correlation betweenOMNs and OMMs with regard to age, gender predis-position, and oral subsites, there is no proof that nevi ofthe oral mucosa are markers of the development of

Fig. 4. Histopathologic features of subepithelial nevus. Allnevomelanocytes are confined within the subepithelial com-partment (hematoxylin-eosin stain, original magnification�50).

malignant melanoma.29

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MelanoacanthomaThe term melanoacanthoma has been used to describe a

rare benign mixed lesion of keratinocytes and pigment-laden dendritic melanocytes.46-48 Oral melanoacanthomais thought to have a reactive nature and usually regressesspontaneously or after incomplete removal, such as inci-sional biopsy.46-48 Approximately 40 cases of oral mela-noacanthoma have been reported.46 Differently from itscutaneous counterpart, oral lesions occur almost exclu-sively in Blacks, affect a much younger population, de-velop rapidly, and generally have a flat surface. The buc-cal mucosa is the most frequently affected subsite.

Tobacco-associated melanin pigmentation(smoker’s melanosis)

Smoking has been found to cause diffuse oral mel-anin pigmentation in European and Asian popula-

Fig. 5. Blue nevus of the palate.

Fig. 6. Histopathologic features of a blue nevus. Spindle-shaped nevomelanocytes (Schmorl stain, original magnifica-tion �150).

tion.49-52 It has been reported in 21.5% of smokers, and

the intensity of the pigmentation is related to the num-ber of cigarettes consumed.51 Some authors have no-ticed a significant increase in gingival melanosis ofchildren with parents who smoke.53 Smoker’s melano-sis seems to be directly related to a stimulant effect ofsubstances in smoke on melanocytes. In parallel to amodel accepted for the skin, some authors hypothesizedthat melanin may play a role in detoxification of poly-cyclic amines nicotine and benzopyrene.49,50

Subsites involved are mainly gingiva, hard palate,buccal and commissural mucosa, inferior surface of thetongue, and lip mucosa (Fig. 7). Smoker’s melanosis isusually black-brown.49-52

From a histologic point of view, increased melaninis found in the basal layer of the epithelium and theremay be melanophages in the subjacent connectivetissue. No melanin is detected in the upper part of theepithelium.54 Smoker’s melanosis does not requiretreatment, and disappearance has been reported aftercessation of the smoking habit.1,49

Malignant melanomaOral malignant melanoma (OMM) is an aggressive

tumor of melanocytes, accounting for 0.5% of alloral malignancies.55,56 The neoplasm is more com-mon in Japan and Africa than in Western coun-tries.57-59 The etiology of OMM is unknown. To-bacco use and chronic mechanical irritation resultingfrom ill-fitting dentures have been mentioned as pos-sible risk factors.57,60 Most OMMs arise de novofrom apparently normal mucosa, but about 30% arepreceded by oral pigmentations for several months oreven years.57,61

The initial symptom and sign of OMM is the emer-gence of a mass lesion which is usually pigmented. TheOMM may be uniformly brown or black or may show

Fig. 7. Smoker’s melanosis of the lower lip.

variation of color, with black, brown, gray, purple, and

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red shades, or depigmentations.62 Satellite foci occa-sionally surround the primary tumor. In amelanoticmelanomas, pigmentation is absent55,56 (Fig. 8). Themost frequently affected oral sites are the palate and themaxillary gingiva.12,62

The OMMs probably originate from junctional me-lanocytes; in their first phase of development, the cellsare restricted to the epithelial compartment: in situmelanoma. Subsequently, melanoma cells invade theunderlying tissues.62 Melanoma cells show a widerange of shapes, including spindle, plasmacytoid, andepithelioid ones. Clear cell change is occasionallyseen.46,62,63

The OMM is not subdivided into the classicalcutaneous melanoma categories, which include su-perficial spreading melanoma, nodular melanoma(NM), and acral lentiginous melanoma (ALM).There is, however, often some similarity betweenALM and NM.12,59,62,64 The histologic microstagingsystem of Clark, used in cutaneous melanoma, cannot be applied to oral mucosa, because of the lack ofhistologic landmarks analogous to papillary and re-ticular dermis.12,62 Tumor thickness does not appearto be associated with prognosis.63 The TNM clinicalstaging system for OMM recognizes three stages:stage I, primary tumor present only (T any N0 M0);stage II, tumor metastatic to regional lymph nodes (Tany N1 M0); Stage III, tumor metastatic to distantsites (T any N any M1).56

In different series, the actuarial 5-year overallsurvival rate for head and neck mucosal melanomaranges from 21% to 40%, and for OMM it is 15%,with a median survival of 25 months.12,58 Gingivalmelanoma has a better 5-year survival rate than pal-atal, with a longer median survival period (46months vs. 22 months, respectively).12 Recurrent

Fig. 8. Amelanotic melanoma of the palate.

melanoma may manifest itself up to 10-15 years after

primary therapy.65 Distant metastases often affectthe lungs, brain, liver, or bones.66

SYSTEMIC DISORDERS ASSOCIATED WITHTHE PRESENCE OF ORAL PIGMENTEDMELANOCYTIC LESIONSPeutz-Jeghers and other familial hamartomasyndromes

The Peutz-Jeghers syndrome consists of mucocu-taneous macules, intestinal hamartomatous polypo-sis, and increased risk of carcinomas of the gastro-intestinal tract, pancreas, breast, and thyroid.67,68

The disease is associated with germline mutations inthe LKB1/STK11 gene located on the short arm ofchromosome 19.68,69

Black-to-brown spots of less than 1 mm in size aretypically localized on the lower lip and in the perioralarea (Fig. 9). Intraoral, intranasal, conjunctival, andrectal pigmented lesions as well as spots localized onthe acral surfaces may also be present.1-3,68

The oral lesions are benign and histologically char-acterized by an increase in melanin in the basal layer,without an obviously increased number of melano-cytes.1,2 A fading or a disappearance of the spots isusually observed in older age.70 Interestingly, periorallesions tend to persist.1

So-called “PTEN hamartoma tumor syndromes”(PHTS), characterized by mutations in the tumor sup-pressor gene PTEN (phosphatase and tensin homologuedeleted on chromosome 10) include several rare dis-eases such as the Ruvalcaba-Myhre-Smith and Cowdensyndromes.68 Perioral lentigines have occasionallybeen reported in these.2

Addison disease and other endocrine disordersPrimary hypoadrenalism caused by autoimmune dis-

ease, infection, or malignancy, also referred to as Ad-

Fig. 9. Perioral involvement in Peutz-Jegher syndrome.

dison disease, is characterized by deficient production

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of hormones of the adrenal cortex, leading to increasedproduction of adrenocorticotropic hormone (ACTH).71

This may result in a diffuse dark pigmentation of theskin and the oral mucosa.2,72 Other signs and symptomsof Addison’s disease include anorexia, nausea, andpostural hypotension.

Lips, gingival, buccal mucosa, hard palate, andtongue are usually involved (Fig. 10). Pigmented le-sions may be diffuse or localized and usually precedeskin manifestations.2,3

Diffuse or discrete pigmentations of the lips and oralmucosa are sometimes observed in monostotic andpolyostotic fibrous dysplasia (McCune-Albright syn-drome), hyperthyroidism, and Nelson syndrome.2

Treatment of pigmented lesions of the oral mucosaassociated with a systemic disorder is usually not re-quired unless discomfort is present. The disappearanceof oral lesions may follow the treatment of the under-lying condition.

Other conditionsOral melanocytic pigmentations have been reported

in patients with Laugier-Hunziker syndrome (idio-pathic lenticular mucocutaneous pigmentations) andwith Carney complex (spotty skin pigmentations, myx-omas. and endocrine overactivity).2,73-77

Human immunodeficiency virus infection has beenassociated with multiple usually well circumscribedmelanotic macules localized on the buccal and palatalmucosa, gingiva, and lips.5 However, the associationmay be only coincidental. The histolopathologic ap-pearance is similar to classical melanotic macules. Itremains unclear whether such pigmentations are causedby the virus, therapy, or other factors.1,2,78

Chronic inflammatory conditions, such as oral lichen

Fig. 10. Oral manifestation of Addison disease (courtesy ofDr. J. van Hooff, The Netherlands).

planus, pemphigus, pemphigoid, and chronic periodon-

tal disease, are sometimes associated with deposition ofmelanin within the connective tissue, resulting in adarkening of the mucosal area.1,4 This phenomenon ismostly observed in dark-skinned individuals.3 Fixeddrug reaction after administration with cotrymazole,tetracycline, colchicine, and ketoconazole also has beenassociated with postinflammatory hyperpigmenta-tion.3,79 It is debatable if these reactions only depend onmelanin.

The presence of lesions resembling melanotic mac-ules of the palate in patients with lung diseases, includ-ing cancer, also has been reported, but there is lack ofevidence of a true association.80 Melanin productionand stimulation may also sometimes follow surgicalprocedures.4

NONMELANIN-ASSOCIATED PIGMENTEDLESIONS OF THE ORAL CAVITYLesions caused by endogenous pigments (blood-related pigmentations)

Extravasations of blood in hematomas, petechiae,purpurae, and ecchymoses may cause pigmentation3,81

as a result of accumulation and degradation of hemo-globin to bilirubin and biliverdin.3 Color of the lesionsdepend on length of time from trauma and may rangefrom red to black. Typical traumatic events in the oralcavity possibly associated with blood extravasationsand hyperpigmentation include biting, traumas witheating, and iatrogenic procedures.

Patients with hemochromatosis (“bronze diabetes”)frequently display bluish-gray pigmentation of the hardpalate, gingiva, and buccal mucosa2,4 (Fig. 11). Thepigmentation is caused by deposition of iron-containingpigments (ferritin and hemosiderin) within the skin andmucous membranes.4 Similarly, a diffuse black-brown

Fig. 11. Palatal pigmentation in a patient with hemochroma-tosis.

pigmentation, most commonly in the junction between

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the hard and soft palate, may be observed in patientswith beta-thalassemia.1

Lesions caused by exogenous pigments (metallicpigmentations)

Amalgam pigmentation (amalgam tattoo). Acciden-tal displacement of metal particles in oral soft tissuesduring restorative dental procedures using amalgammay result in amalgam pigmentation, the so-called“amalgam tattoo.”1-5 Terms such as focal argyrosis ororal localized argyria should be avoided, because notonly silver, but also mercury and tin, are contained inthe amalgam alloy.

Despite the high prevalence of these lesions amongthe general population, little information is available inthe dental literature. Buchner and Hansen identified 268(1.3%) amalgam tattoos among 20,731 specimens fromthe oral cavity.82

The cause of amalgam tattoos can be iatrogenic ortraumatic. Metal particles may over time leach into thesoft oral tissues, resulting in the discoloration. Buchnerand Hansen82 and Owens et al.83 listed several iatro-genic and traumatic modalities through which amalgammay be introduced in the oral tissues: condensation ofthe material in abraded mucosa during routine amalgamrestorative work, introduction of the material within thelacerated mucosa during removal of amalgam fillings orcrowns and bridges, introduction of broken pieces intoa socket or the periosteoum during extraction of teeth,and introduction of metal particles in a surgical woundduring root canal treatment with a retrograde amalgamfilling.82,83

Amalgam tattoos usually range from 0.1 up to(rarely) 2 cm in size and can be solitary or multiple.Colors reported are blue, gray, or black with a spec-trum of variegation depending on the depth of metalwithin tissues. Gingiva and alveolar mucosa are thesubsites most frequently involved. In alveolar eden-tulous ridges, amalgam tattoos can also be associatedwith restored antagonistic teeth (Fig. 12). The diag-nosis is based on clinical findings and the relation-ship with present or removed amalgam restorations.

Radiographic features may show localized radiopac-ities.1 Biopsy is indicated only when suspicion ofOMM can not be ruled out on clinical grounds alone.Histopathologic investigation reveals amalgam parti-cles dispersed in the connective tissue and sometimes inthe walls of vessels. These particles may also line thebasement membrane of the surface epithelium. Brown-ish granules within phagocytic cells and fibroblastscytoplasm can also be observed.82,84,85 A spreading ofthese pigmented lesions mediated by local migration ofphagocytic cells containing metal has also been de-

scribed.1-3,82-84 Histopathologic examination of an

amalgam tattoo is usually diagnostic because of the sizeand shape of the metal particles and the way they arespread in the tissue. However, in rare cases, one mayneed additional stains. The common melanin and ironstains are often not sufficient for differentiating be-tween metal particles and melanin pigment. Instead,immunohistochemical markers such as HMB-45 andMelan A are more suitable for this purpose. Whendealing with metal pigmentation, one may be able toidentify the type of metal(s) by using electron-probemicroanalysis.

There is no indication for complete removal of anamalgam tattoo.

Accidental or voluntary introduction of other foreignparticles include graphite from pencil tips, tattoo inks,and chronic contact with charcoal toothpaste and veg-etables such as Juglans regia, Cola nitida, and Cathaedulis.1,2,86

Heavy metals. Systemically absorbed metals mayinduce discoloration of the oral mucosa, caused byperipheral metal accumulation. These conditions werefrequent in the past as result of occupational exposuresto certain drugs. Arsenic, lead, bismuth, mercury, sil-ver, and gold are the metals most frequently in-volved.1-5

Bismuth was typically used for the treatment ofsyphilis, and its administration was associated withdiffuse oral pigmentation and formation of a blue-black line at the marginal gingiva.1 A characteristicfeature of plumbism (lead poisoning) is the so-called“burtonian line,” a gray linear area of discolorationbelow the gingival margin1,3,4 (Fig. 13). Silver (ar-gyria) and gold (chrysiasis) may produce slate-grayoral pigmentation and purple gingival discoloration,respectively.2

Heavy metal intoxication can be associated with a

Fig. 12. Amalgam tattoo.

wide range of systemic signs and symptoms.1,3

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DRUGS ASSOCIATED WITH PIGMENTEDLESIONS OF THE ORAL CAVITY (EXCLUDINGHEAVY METAL CONTAINING DRUGS)

Many nonheavy metal–containing drugs can inducediscoloration of oral tissues.1-5,87 Direct deposition onoral surfaces, local accumulation after systemic absorp-tion, stimulation of melanin-related pathways, and bac-terial metabolism, alone or in combination, may resultin oral pigmentations. The most commonly reporteddrugs are listed in Table I.

DISCUSSION AND PROPOSAL OF A FLOW-CHART

Diagnosis of pigmented lesions of the oral cavity andperioral tissues is challenging.1-5 Even though epide-miology may be of some help in orientating the clini-cian and even though some lesions may confidently bediagnosed on clinical grounds alone, such a diagnosisremains “provisional.” Definitive diagnosis usually re-quires histopathologic evaluation. Occasionally, immu-nohistochemical stains such as melanocyte markerHMB-45 and macrophage marker CD68 may be re-quired to arrive at a correct diagnosis.

With the exception of OMM, all pigmented primarylesions in the oral cavity are benign, and treatmentusually is required only when discomfort is present. Noreliable criteria exist for the clinical differentiation be-tween OMM and a number of other pigmented lesions,such as melanotic macules, oral melanocytic nevi, andamalgam tattoos.1-5

The so-called ABCD checklist (asymmetry, borderirregularities, color variegation, and diameter �6mm) that is commonly used to aid in the identifica-tion of cutaneous melanoma may be of some help inthe clinical diagnosis of oral melanoma.88,89 Rapidlygrowing pigmented lesions should always be biop-

Fig. 13. Oral manifestation of lead poisoning (“burtonianline”).

sied.1

Location on the palate increases the rate of suspicion ofmelanoma and usually requires a biopsy or long-termfollow-up. When located on the gingiva, the main differ-ential diagnosis is between amalgam tattoo and mela-noma. In case of the slightest doubt a biopsy should be taken.

In Fig. 1 a flow-chart is depicted that may help theclinician in the diagnostic pathway of pigmented le-sions of the oral cavity. When history allows classify-ing a lesion as melanocytic, a subclassification shouldbe made according to the clinical suspicion of malig-nancy (ABCD checklist, recent history, age, and subsiteinvolved). Lesions presenting no or low suspicion ofmalignancy may be confidently diagnosed on clinicalgrounds alone (e.g., oral manifestations of systemicdiseases, physiologic pigmentations, or smoker’s mel-anosis) or may require histopathologica evaluation.

Some nonmelanocytic lesions, such as ethnic tattoos orpigmentations associated with heavy metal poisoning, areeasily recognized on clinical grounds (e.g., burtonianline). In other cases, such as bluish discolorations notclearly related to amalgam restorations and/or not show-ing radiologic signs for the presence of metal particles, his-topathologica evaluation is needed to reach a firm diagnosis.

A biopsy or referral to a specialist for further evaluationis indicated if the history does not allow distinguishingbetween melanocytic and nonmelanocytic lesion.

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Reprint requests:

Prof. Isaäc van der WaalVrije Universiteit Medical Center/ACTAP.O. Box 70571107, MB, AmsterdamThe Netherlands

i.vanderwaal@vumc.nl