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Prevalence and clinical features of pigmented oral lesions

ARTICLE in INTERNATIONAL JOURNAL OF DERMATOLOGY · DECEMBER 2015 Impact Factor: 1.31 · DOI: 10.1111/ijd.13133

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Yazan Hassona Faleh Sawair University of Jordan University of Jordan

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All in-text references underlined in blue are linked to publications on ResearchGate, Available from: Faleh Sawair letting you access and read them immediately. Retrieved on: 25 February 2016 Report Prevalence and clinical features of pigmented oral lesions

Yazan Hassona1, BDS, FFDRCSI, PhD, Faleh Sawair1, PhD, Omar Al-karadsheh1, DClinDent, and Crispian Scully2, MD, PhD

1Department of Oral and Maxillofacial Abstract Surgery, Oral Medicine and Periodontology, Background To examine the relative prevalence, types, and clinical features of pigmented Faculty of Dentistry, The University of lesions of the in 1275 patients attending a university hospital for dental care. Jordan, Amman, Jordan, and 2University Methods Patients attending dental clinics at The University of Jordan Hospital over a College London, London, UK 1-year period were examined for the presence of oral pigmentations. Histopathological Correspondence examination was performed on focally pigmented lesions with a suspicious or uncertain Yazan Hassona, BDS, FFDRCSI, PhD clinical diagnosis. Assistant Professor of Oral Medicine and Results A total of 386 (30.2%) patients were found to have oral pigmentations. Of these, Special Needs Dentistry racial pigmentation (39.9%) and smokers’ melanosis (32.9%) were the most common Faculty of Dentistry The University of Jordan causes of oral pigmentations. Other causes included (18.9%), focal Queen Rania Street melanotic macules (5.7%), postinflammatory pigmentation (1.6%), pigmentation due to PO Box 11942, Amman medications or systemic disease (0.52%), heavy metal deposits (0.26%), and oral nevus Jordan (0.26%). Gingivae and buccal mucosae were the most common sites for oral E-mails: [email protected] or pigmentations. [email protected] Conclusion Pigmentations of the oral mucosa are common. Gingivae and buccal mucosae Conflicts of interest: None. are the most common sites for oral pigmentations. Proper history and recognition of clinical features are important for effective management. doi: 10.1111/ijd.13133

metal pigmentation, and melanosis associated with various Introduction systemic diseases5 (Fig. 1). The color of the oral mucosa varies depending on degree The literature is replete with studies about prevalence of of keratinization, thickness, vascularization, number and oral mucosal lesions in different populations from both – activity of melanocytes, and type of submucosal tissue.1 developed and developing countries.6 9 However, only a The physiologic color of oral mucosa ranges from red– few studies specifically examined the relative frequency of purple in light-skinned people to dark brown in dark- pigmented oral lesions.10,11 For example, De Giorgi skinned people.1,2 Melanin is produced by melanocytes in et al.,10 reported that the prevalence of solitary pigmented the epithelial basal layer and transferred via melanosomes oral lesions in patients attending a dermatology center in to adjacent keratinocytes.3 The amount of melanin is Italy as 5.7%. Buchner et al.,11 reviewed a total of 89,430 genetically determined; however, various stimuli such as oral mucosal biopsies from patients in Israel and reported a trauma, inflammation, hormones, medications, and radia- 0.83% prevalence of solitary pigmented oral lesions. tion may result in an increased melanin production.3 The availability of data about types, prevalence, and Pigmented mucosal lesions are common in the mouth. clinical features of pigmented oral lesions could help Accurate diagnosis can be challenging because such lesions healthcare professionals in their diagnosis. The purpose may result from a variety of causes, both exogenous and of this study therefore was to examine types, clinical fea- endogenous, including physiologic, reactive, neoplastic, tures, and relative frequency of pigmented oral lesions in systemic, and idiopathic processes.4 Pigmented lesions of a group of patients attending a university hospital for the oral mucosa can be classified clinically into focal pig- dental care. mentations (e.g., oral melanotic macule, amalgam tattoo, melanocytic nevus, melanoma, and melanoacanthoma) and Materials and methods multifocal or diffused macular pigmentations, including entities such as physiologic (ethnic) pigmentation, drug-in- The Faculty of Dentistry Research and Ethics Committee duced melanosis, smoking-associated melanosis, heavy (FDREC) at the University of Jordan, Amman, reviewed and 1

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Figure 1 Differential diagnoses. and typical clinical features of pigmented oral lesions.

approved the study, which was conducted over a12-month Diagnostic biopsies were obtained under local anesthesia in period (from February 2014 to February 2015). The research patients with focally pigmented lesions with uncertain clinical was conducted in full accordance with the World Medical diagnosis and in cases demonstrating suspicious clinical Association Declaration of Helsinki. features such as irregular borders, large size (>6 mm), New adult patients attending dental clinics at The University asymmetry, and color variations. In addition, diagnostic biopsies of Jordan Hospital were examined for the presence of oral were obtained in all cases that presented with solitary raised mucosal pigmentation by a single oral medicine specialist (YH) lesions, or when patients reported a change in size or color. according to the World Health Organization method.12 All Consent was obtained from all patients before biopsy. patients provided formal informed consented. The diagnosis of Statistical analysis was performed using GraphPad Prism 6.0 pigmented oral lesions considered clinical features such as the (GraphPad Software Inc., La Jolla, CA, USA). Frequency number, distribution, site, size, shape, color of the lesion, and distributions were obtained, and chi-squared and Student t-tests its relation to metal-filled teeth. The history included inquiries were used to compare differences between groups. Statistical about the onset and duration of the lesion, presence of significance was set at P < 0.05. associated skin hyperpigmentation, use of prescription and over-the-counter medications, family history of pigmentary Results disorders, and presence of systemic signs and symptoms (e.g., fever, malaise, fatigue, weight loss, abdominal pain, The study population consisted of 1275 (704 females and gastrointestinal upset). Data about social habits such as 571 males) adult dental patients whose main characteris- smoking, narghile (shisha) use, and alcohol consumption were tics are summarized in Table 1. The mean age of patients obtained from all participants. Patients with pigmented oral was 39.2 Æ 12.6 years (range: 18–86 years). Of the total lesions were also asked about any associated symptoms and group investigated, 34.8% were smokers and 7.3% whether they were aware of the presence of oral pigmentations. reported alcohol consumption (Table 1). A total of 386

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Table 1 Demographic characteristics of patients in study

n %

Gender Male 571 46.1 Female 704 53.9 Age <35 590 46.3 35–55 415 32.6 >55 269 21.1 Tobacco 443 34.8 Cigarettes 221 17.4 Narghile 142 11.2 Both 79 6.2 Alcohol 93 7.3

(30.3%) patients (246 males and 140 females) were found to have oral pigmentations. The mean age of patients with pigmented oral lesions was 41.3 Æ 11.1 years. More than half (53.1%) of these patients smoked tobacco, and 2.3% consumed alcohol. The presence of oral mucosal pigmentations was significantly associated with male gen- der and history of smoking (P < 0.05). No significant association was found between the presence of oral pig- > mentations and age or alcohol consumption (P 0.05). Figure 2 Relative frequency of oral pigmented lesions in None of the patients diagnosed with oral mucosal pig- study patients. mentations reported a family history of melanoma or other pigmentary disorder. Diffuse or multifocal pigmentation was identified in the majority of cases (75.2%), while a focal pattern was identi- fied in 24.8%. Overall, the gingiva (56.2%) and buccal mucosa (39%) were the most commonly affected sites, and other affected sites included labial mucosa (31.5%), tongue (6.9%), (5.9%), lower vermilion (4.7%), floor of the mouth (1.1%), and upper vermilion (0.9%). Racial pig- mentation and smoker’s melanosis were the most common causes of oral pigmentations. Other causes included amal- gam tattoo, focal melanotic macules, postinflammatory pigmentation, pigmentation due to medications or systemic disease, heavy metal deposits, and oral nevus (Fig. 2). Most Figure 3 Racial (physiologic) pigmentation presenting as well-defined dark brown band on the attached gingiva. cases were diagnosed solely based on history and clinical features; diagnostic biopsies were obtained in 21 lesions (5.2%) presented with uncertain clinical diagnosis or with exhibited a multifocal pattern of homogeneous bilaterally suspicious clinical features. Melanoacanthoma and mela- symmetrical brownish pigmentation (Fig. 3). Gingiva was were not encountered in this study. affected in most cases (72%), and other affected sites None of the patients with pigmentations reported any included buccal mucosa (46%), labial mucosa (26%), symptoms, and only 92 patients (23.8%) were aware of tongue (13%), and palate (4%). the existence of oral pigmentation. Female patients were more likely than males to be aware of oral mucosal pig- Smoker’s melanosis mentation (P < 0.05). Smoker’s melanosis was encountered in 127 patients (102 males and 25 females; P < 0.05). Labial mucosa was the Racial (physiologic pigmentation) most commonly affected site (63%) followed by buccal Racial pigmentation was encountered in 154 patients (97 mucosa (56%), gingiva (31%), palatal mucosa (13.2%), males and 57 females; P < 0.05). Racial pigmentation and tongue (4%). Smoker’s melanosis appeared as

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multifocal gray to brown patches with random distribu- melanotic macules in the lower vermilion (82%). Other tion and irregular pattern (Fig. 4). affected sites included gingivae (10%), upper vermilion (4%), and buccal mucosae (4%). Melanotic macules Amalgam tattoos appeared as small (2–6 mm) well-circumscribed brown to Seventy-three patients (36 males and 37 females; black macules (Fig. 6). P > 0.05) had amalgam tattoos. Amalgam tattoos appeared as small (2–8 mm) blue to gray macules, mainly Postinflammatory pigmentation on the gingivae adjacent to amalgam-filled teeth. Few Postinflammatory pigmentation was encountered in six cases (9.5%) were encountered at atypical sites such as cases (four females and two males). Five patients had oral palate, buccal mucosa, and floor of the mouth. Excisional , and one had vulgaris. Postin- biopsy of such cases confirmed the diagnosis of amalgam flammatory pigmentation appeared as multifocal light tattoo (Fig. 5). brown patches at sites of mucosal inflammation (Fig. 7).

Melanotic macules Pigmentation due to systemic disease or medications We observed 22 cases (14 females and eight males; We encountered two cases of oral pigmentations due to P > 0.05) of melanotic macules. Most cases were labial systemic diseases or medications. One patient was a 28- year-old woman diagnosed with Addison’s disease 1 year before presentation. The pigmentation appeared as dif- fused faint brown patches on the lateral borders of the tongue and both buccal mucosae (Fig. 8); macular pig- mentations were also seen on dorsal hands and palms. The other patient was a 33-year-old woman using proges- terone–estrogen-based oral contraceptive pills. The pig- mentation appeared as diffuse macular pigmentations mainly on the upper and lower labial mucosae (Fig. 9).

Pigmentation due to heavy metals We encountered one case of pigmentation due to heavy metals. The patient was a 42-year-old non-smoker male working in a battery factory for 7 years. The pigmenta- tion appeared as a linear blue–gray patch on the lower labial gingiva (Fig. 10). No pigmentations were encoun- tered at other mucosal sites. Although no formal measure- ment of blood lead level was performed, the patient demonstrated clinical features suggestive of lead toxicity, including headache, constipation, and numbness of the Figure 4 Smoker’s melanosis presenting as diffuse brown extremities. Blood film showed hypochromic microcytic patches with irregular distribution on the buccal mucosa. anemia with basophilic stippling of red blood cells.

(a) (b)

Figure 5 Amalgam tattoo at atypical site. (a) Blue–gray macule on the floor of the mouth. (b) Histopathological examination showed scattered arrangement of dark solid fragments along blood vessels and collagen fibers. No significant chronic inflammation was noticed (hematoxylin and eosin stain, 9 20, 9 140).

International Journal of Dermatology 2015 ª 2015 The International Society of Dermatology Hassona et al. Oral pigmentations Report 5

Figure 6 Melanotic macule on upper vermilion.

Oral nevus One patient, a 38-year-old woman, had an oral nevus. It appeared as an elevated well-circumscribed black nodule (6 mm in diameter) on the right buccal mucosa. Exci- sional biopsy showed proliferation of benign hypermelan- otic cells arranged in compact nests in the subjacent Figure 8 Diffuse brown pigmentation on the tongue of a patient with Addison’s disease connective tissue (intramucosal nevus) (Fig. 11).

Similar to other studies, we identified racial (physio- Discussion logic pigmentation) and smoker’s melanosis as the main – There is paucity of information in the literature regarding causes of oral mucosal pigmentation.10,11,13 16 The the relative prevalence of oral mucosal pigmentations, amount of melanin produced by melanocytes is geneti- despite the high frequency. The present study examined cally determined, and several pathways, including the the relative frequency, types, and clinical features of pig- adrenalin/b2-adrenoceptor/cAMP/MITF pathway, a-MSH/ mented oral lesions in 1275 patients attending dental clin- MC1R/cAMP/MITF pathway, and b-endorphin/l-opioid ics at the University of Jordan Hospital, which is the receptor/PKCb isoform signaling pathway, have been main public hospital in Jordan attended by patients from identified as main regulators.17,18 Substantial variations in various socioeconomic backgrounds. The overall preva- the degree of melanin pigmentations exist between per- lence of oral mucosal pigmentation in our study was sons from different racial backgrounds.3 Oral racial pig- 30.2%. mentations are more frequently encountered in dark-

(a) (b)

Figure 7 Postinflammatory pigmentation in a patient with history of oral lichen planus. (a) Diffuse brown pigmentation with reticular pattern on buccal mucosa. (b) Histopathological examination showed deposition of melanin in the lamina propria along with chronic inflammatory cell infiltrate (hematoxylin and eosin, 9 20, 9 40).

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A stimulant effect of tobacco constituents on melano- cytes has been proposed as a possible mechanism for tobacco-associated oral pigmentation (smoker’s melano- sis).3 It has been hypothesized that melanin may play a role in the detoxification of polycyclic amines and benzopyre- nes;20,21 smoker’s melanosis might therefore represent a mucosal protective mechanism from the harmful effects of smoking. Clinical distinction between smoker’s melanosis and racial pigmentation might be difficult in some cases because both conditions present as diffused brown pigmen- tations involving mainly the gingivae and labial and buccal mucosa. A history of lesion evolution and smoking habits might help to distinguish between the two conditions. In Figure 9 Diffuse macular brown pigmentation on upper and labial mucosa in a patient receiving oral contraceptives. addition, racial pigmentation tends to be homogeneous and bilaterally symmetrical, while smoker’s melanosis exhibits an irregular or a random pattern of distribution. Less commonly, diffuse oral pigmentation might result from systemic diseases or as an adverse effect of medica- tions. In the present study, we encountered a patient with oral pigmentation due to Addison’s disease and one due to oral contraceptives. Although Addison’s disease is relatively uncommon, hyperpigmentation of skin and mucosal sur- faces can occur in up to 92% of affected patients.22 Hyper- pigmentation associated with Addison’s disease occurs due to overproduction of lipotropin, a proopi- omelanocortin by-product, which is secreted in excess amounts concomitantly with corticotropin from the pitu- itary gland because of the lack of feedback inhibition.23 Figure 10 Heavy metal pigmentation due to lead toxicity The clinical appearance of Addisonian oral mucosal pig- presenting as diffuse linear blue patches on the attached mentation is not specific and appears similar to other gingiva. causes of diffuse oral pigmentation such as smoking and physiologic pigmentation. The presence of systemic fea- skinned populations, and several studies have reported a tures of adrenal insufficiency, such as hypotension, cuta- correlation between skin color and oral mucosal pigmen- neous pigmentation fatigue, orthostasis, weight loss, and tation.14,19 nausea, might help distinguish this type of pigmentation,

(a) (b)

Figure 11 Oral melanocytic nevus (intramucosal type). (a) Brown nodule on the right buccal mucosa. (b) Histopathological examination showed superficial epithelioid-like oval cells with abundant cytoplasm and large round or oval nuclei containing melanin pigmentation (type A nevus cells) and lymphoid-like cells (type B nevus cells) in the middle portion of the lesion containing no melanin (hematoxylin and eosin, 9 20, 9 40).

International Journal of Dermatology 2015 ª 2015 The International Society of Dermatology Hassona et al. Oral pigmentations Report 7 but reduced serum cortisol levels would confirm the be a cause for oral mucosal pigmentation. This typically diagnosis. Diffuse oral mucosal pigmentation has also presents as a bluish-black line, known as Burton’s line, been reported in association with other systemic diseases, along the gingival margin and seems to be proportional including Puetz–Jeghers syndrome, Laugier–Hunziker to the amount of gingival inflammation.33 In cases with syndrome, McCune–Albright syndrome, Cowden syn- little or no gingival inflammation, other oral sites, such as drome, Carney complex, AIDS, hemochromatosis, Nel- the attached gingiva and buccal mucosa, might be – son syndrome, and hyperthyroidism.24 32 Many drugs affected. The diagnosis of such cases can be challenging; can induce diffuse pigmentation of oral mucosa, includ- however, a history of occupational or environmental ing quinine derivatives, antineoplastic drugs, antiretroviral exposure to heavy metals, and recognition of clinical drugs, oral contraceptives, anticonvulsants, minocycline, signs and symptoms of heavy metal toxicity can help to amiodarone, premarin, and clofazamine.33 The pathogene- reach the correct diagnosis, and measurement of blood sis of drug-induced pigmentation varies according to the levels of the suspected heavy metal will confirm the diag- causative drug and includes deposition of drug or its nosis. Longstanding inflammatory mucosal diseases can metabolites, stimulation of melanin-related pathways, or cause mucosal pigmentation, sometimes called pigmentary bacterial metabolism, alone or in combination.4,34 Drug-in- incontinence.33 In the present study, we identified six duced pigmentation can range from brown (e.g., with oral cases of oral mucosal pigmentation due to chronic oral contraceptives) to blue–black (e.g., hydroxychloroquine). mucosal diseases, primarily lichen planus. The pathogene- Heavy metals, such as lead, bismuth, mercury, gold, sis of this type of pigmentation remains unclear, but there arsenic, cooper, cobalt, chromium, and magnesium, can is increased production of melanin, possibly induced by

Figure 12 Evaluation and management of pigmented oral lesions. *Palate and gingivae are considered subsites at risk for melanoma development.

ª 2015 The International Society of Dermatology International Journal of Dermatology 2015 8 Report Oral pigmentations Hassona et al.

the chronic inflammatory microenvironment and accumu- Conclusions lation of melanin-laden macrophages in the superficial layer of connective tissue.33 Oral mucosal pigmentations, particularly physiologic pig- Focal pigmented lesions of oral mucosa are relatively mentation and smoker’s melanosis, are common. Focal uncommon, and reported prevalences range from 0.83 to causes, including amalgam tattoo, melanocytic nevi, and 5.7%.10,11 The prevalence of solitary pigmented oral melanotic macules, are less common. Recognition of clini- lesions in our study was 7.2%. Similar to other studies, cal features is important for effective management. amalgam tattoos and melanotic macules were the main Detailed history, including family history, medical his- – causes of focal oral pigmentation.13 15 An amalgam tat- tory, social history, environmental and occupational his- too results from accidental or iatrogenic implantation of tory, and history of previous trauma and dental amalgam particles into oral soft tissues during dental pro- treatment, is essential in all cases. Histopathological cedures, resulting in bluish-gray macular pigmentation examination is necessary when the clinical diagnosis is often near an amalgam-filled tooth. Findings of our study uncertain or when lesions exhibit suspicious features such confirmed that gingivae and alveolar mucosa are the most as an increase in size, non-homogeneous color, irregular common sites for amalgam tattoo.35,36 Occasionally, borders, and change in color, rapid growth, ulceration, amalgam tattoos appear in atypical sites such as palate bleeding, or pain (Fig. 12). and floor of the mouth. In these cases, particularly when a radiograph fails to show any evidence of the radiopaque Acknowledgments remnants of amalgam, excisional biopsy might be needed to confirm the diagnosis. Histologically, the amalgam tat- The authors would like to thank Mrs. Najwa Yaseen for too appears as discrete dark granules or fragments help in administrative work. arranged mainly around collagen bundles and blood ves- sels causing little inflammatory reaction.35,36 Inquiry References about previous history of trauma, particularly with pen- 1 Scully C, Felix DH. 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