Pigmented of the

Eric T. Stoopler and Faizan Alawi

Abstract contemporary perspective of pigmented Pigmented lesions of the oral mucosa are lesions of the oral mucosa and is intended to encountered on a routine basis in clinical prac- serve as a practical clinical resource for oral tice. Oral health-care providers must assess health-care providers. several parameters associated with pigmented lesions, such as location, shape, color, and size. Keywords Etiology of pigmented lesions may be attrib- Oral mucosa • Pigmentation • • Focal • uted to a local phenomenon and/or associated Multifocal • Diffuse • Systemic • Genetic • with an underlying systemic disorder. Diag- Exogenous nostic and therapeutic modalities must be care- fully considered as these lesions encompass the Contents spectrum of clinical pathology, ranging from Introduction ...... 2 benign to malignant. Clinicians should conduct a thorough medical history and relevant phys- Focal Pigmentation ...... 2 /Ephelis ...... 2 ical examination for patients with pigmented Oral/Labial Melanotic Macule ...... 3 lesions to identify possible adrenal, gastroin- Oral Melanoacanthoma ...... 5 testinal, or genetic disorders that are commonly Melanocytic ...... 6 associated with these types of lesions. If a Malignant ...... 8 systemic disorder is suspected, the patient Multifocal/Diffuse Pigmentation ...... 14 should be promptly referred to the appropriate Physiologic Pigmentation ...... 14 health-care provider for further evaluation and Drug-Induced ...... 15 Smoker’s Melanosis ...... 16 management. Multidisciplinary care is often Post-inflammatory (Inflammatory) necessary to effectively manage patients with ...... 17 these conditions. This chapter provides a Laugier-Hunziker Pigmentation ...... 18 Pigmentation Associated with Systemic or Genetic Disorders ...... 19 Adrenal Insufficiency (Addison Disease) ...... 19 * E.T. Stoopler ( ) Cushing Disease ...... 21 Department of Oral Medicine, University of Pennsylvania Human Immunodeficiency Virus (HIV): Associated School of Dental Medicine, Philadelphia, PA, USA Pigmentation ...... 23 e-mail: [email protected] Peutz-Jeghers Syndrome ...... 24 F. Alawi Exogenous Causes of Clinical Pigmentation ...... 26 Department of Pathology, University of Pennsylvania : Amalgam, Graphite, and Ornamental ...... 26 School of Dental Medicine, Philadelphia, PA, USA Metal-induced Discoloration ...... 28 e-mail: [email protected]

# Springer International Publishing AG 2017 1 C.S. Farah et al. (eds.), Contemporary Oral Medicine, DOI 10.1007/978-3-319-28100-1_17-1 2 E.T. Stoopler and F. Alawi

Conclusion and Future Directions ...... 28 systemic or genetic disorders, and exogenous Cross-References ...... 29 causes of clinical pigmentation (Table 1). are derived from neural crest cells References ...... 29 and are located in the basal epithelial layer of squamous mucous membranes (Meleti et al. Introduction 2008). The functions of melanocytes are not fully understood, but the melanin produced by these cells absorb ultraviolet light, scavenge The mucous membranes lining the oral cavity are reactive oxygen species, and determine skin, hair, not uniformly colored and dependent upon the spe- and eye color (Meleti et al. 2008; Feller et al. cific anatomic location; healthy tissue commonly 2014a, b). Oral melanocytes are regularly inter- ranges in color from white to red-purple. This is due spersed between basal keratinocytes, and melanin to the interaction of various tissues that compose the from the melanocytes are transported and trans- mucosal lining, including presence or absence of mitted to epithelial cells via dendritic migration of keratin on the surface epithelium, location and pres- melanosomes (melanin-containing vesicles). The ence of vascular structures in the stroma, existence ratio of melanocytes to keratinocytes in the basal of adipocytes, and the lack of melanin pigmentation epithelial layer ranges from 1:10 to 1:15 (Feller in the basal cell layer of the epithelium. Pigment et al. 2014a, b). Two chemically distinct types of deposition, whether physiologic or pathologic, or melanin exist, eumelanin (brown-black) and attributed to endogenous or exogenous substances, pheomelanin (red/yellow), and melanogenesis is will impart gray, blue, brown and/or black color considered a mixed process between these mela- changes to the oral mucosa. The most common nin types, with proportions of eumelanin and endogenous sources of pigmentation are melanin, pheomelanin being genetically determined (Feller hemoglobin, and hemosiderin, while exogenous et al. 2014a, b). There are no numerical or struc- sources of pigmentation are usually attributed to tural differences in oral melanocytes between traumatic or iatrogenic events that result in deposi- tion of foreign material directly into the mucosal Table 1 Pigmented lesions of the oral mucosa tissues. Several parameters associated with I. Focal pigmentation conditions pigmented lesions, such as location, shape, color, a. Freckle/ephelis and size, must be assessed in order for clinicians to b. Oral/labial melanotic macule appropriately evaluate and manage the condition, as c. Oral melanoacanthoma pathology of pigmented lesions ranges from benign d. to malignant. Clinicians should conduct a thorough e. Malignant melanoma medical, family, and social history, as well as a II. Multifocal/diffuse pigmentation conditions relevant physical examination for patients with a. Physiologic pigmentation pigmented lesions, to identify possible adrenal, gas- b. Drug-induced melanosis trointestinal, or genetic disorders that are commonly c. Smoker’s melanosis associated with these types of lesions. If a systemic d. Post-inflammatory (inflammatory) hyperpigmentation disorder is suspected, the patient should be e. Laugier-Hunziker pigmentation promptly referred to the appropriate health-care III. Pigmentation associated with systemic or genetic provider for further evaluation and management. disorders fi Multidisciplinary care is often necessary to effec- a. Adrenal insuf ciency (Addison disease) b. Cushing disease tively manage patients with these conditions. This c. Human immunodeficiency virus (HIV) – associated chapter provides a contemporary perspective of pigmentation pigmented lesions of the oral mucosa focusing on d. Peutz-Jeghers syndrome those associated with melanin and will discuss focal IV. Exogenous causes of clinical pigmentation pigmentation conditions, multifocal or diffuse pig- a. Tattoos – amalgam, graphite and ornamental mentation conditions, pigmentation associated with b. Metal – induced discoloration Pigmented Lesions of the Oral Mucosa 3 light-skinned and dark-skinned individuals except above the skin surface, and are asymptomatic that in the latter, the melanosomes are larger and (Gaeta et al. 2002; Hatch 2005). They often more numerous (Feller et al. 2014a, b). Several appear on the perioral skin and vermillion border factors likely determine intraoral mucosal color, of the with increased frequency on the lower including number and melanogenic activity of (Hatch 2005). Although many individuals melanocytes, differences in number, size and dis- have less than ten lesions, due to the great vari- tribution of melanosomes, difference in the type ability in the number of lesions present, some may of melanin, and the masking effect of heavily have hundreds of (Gaeta et al. 2002; keratinized epithelium (Feller et al. 2014a, b). Hatch 2005). Histopathologically, freckles exhibit abundant melanin deposition in the basal cell layer of the epidermis without elongation of rete Focal Pigmentation ridges (Hatch 2005).

Freckle/Ephelis Patient Management Treatment is typically not indicated for freckles in Epidemiology childhood or adolescence (Hatch 2005). Sun- A freckle (ephelis) is a hyperpigmented macule screens may help prevent darkening of existing commonly observed on the facial and perioral lesions and prevent the appearance of new lesions skin. They usually develop during the first decade (Bliss et al. 1995). Freckles of cosmetic concern of life and are more common in light-skinned may be treated with chemical peels, laser therapy, individuals with blonde or red hair (Gaeta et al. and/or cryotherapy. MC1R gene variants have 2002; Hatch 2005). There is no gender predilec- been associated with an increased risk for spo- tion, and the color intensity and frequency of radic cutaneous melanoma (Pasquali et al. 2015). freckles typically decrease after adolescence (Gaeta et al. 2002; Hatch 2005). Oral/Labial Melanotic Macule Etiology Freckles are thought to be developmental in origin Epidemiology (Gaeta et al. 2002; Hatch 2005). Genetic poly- A melanotic macule is a benign pigmented morphisms associated with the melanocortin-1 that may occur on intraoral mucosal surfaces (oral receptor (MC1R) gene and chromosome 4q32- melanotic macule) or on the lips (labial melanotic q34 have been strongly associated with freckle macule) (Tarakji et al. 2014). They are considered development (Bastiaens et al. 2001). to be the most common oral mucosal lesions of melanocytic origin and are also termed focal Pathophysiology melanosis (Alawi 2013; Muller 2010). Oral/labial Freckles are due to an increase in melanin produc- melanotic macules are present in up to 3% of the tion without an increase in the number of melano- population, are typically observed in patients in cytes and become more pronounced after sun the fourth and fifth decades, and have a 2:1 female exposure. They are also associated closely with a predilection (Hatch 2005; Meleti et al. 2008; history of symptomatic childhood sunburns (Bliss Muller 2010). et al. 1995). Etiology Clinical-Pathologic Features The etiology of oral/labial melanotic macules has Freckles appear as a uniformly tan- or brown- not been definitively determined but may repre- colored, oval or round macule, between 1 and sent a reactive or a physiologic process (Meleti 3 mm in size on sun-exposed cutaneous surfaces et al. 2008). (Gaeta et al. 2002; Hatch 2005) (Fig. 1). They have regularly defined borders, are not elevated 4 E.T. Stoopler and F. Alawi

Fig. 1 Freckle (ephelis) [arrow] on the facial skin Fig. 3 Biopsy-proven melanotic macule appearing as an irregular brown pigmented lesion along the edentulous mandibular alveolar ridge (Photo courtesy: Professor Camile Farah, Perth Oral Medicine & Dental Sleep Centre, Perth, WA, Australia)

Fig. 2 Biopsy-proven gingival melanotic macule appearing as brown pigmented lesion involving the inter- dental gingiva between 41 and 42 (Photo courtesy: Profes- sor Camile Farah, Perth Oral Medicine & Dental Sleep Centre, Perth, WA, Australia)

Pathophysiology Oral/labial melanotic macules are caused by an increased production and deposition of melanin Fig. 4 Biopsy-proven melanotic macule appearing as a faint brown lesion on the right soft (Photo courtesy: within the basal cell layer, the lamina propria, or Professor Camile Farah, Perth Oral Medicine & Dental both (Meleti et al. 2008). The etiology of these Sleep Centre, Perth, WA, Australia) lesions is unclear; however, sun exposure does not appear to be a precipitating factor. 1993; Shen et al. 2011). Overall, labial melanotic macules are the most common type of macules Clinical-Pathologic Features observed with the lower lip vermillion border Oral/labial melanotic macules are solitary, well- predominantly affected (Kaugars et al. 1993; circumscribed lesions that are typically less than Shen et al. 2011). In contrast to freckles, labial 1 cm in diameter (Alawi 2013; Kauzman et al. melanotic macules do not darken after exposure to 2004). They are uniformly tan to dark brown, the sun (Lim et al. 2014; Meleti et al. 2008). Oral round or oval, and asymptomatic (Kaugars et al. melanotic macules may appear on any surface but Pigmented Lesions of the Oral Mucosa 5

Fig. 5 Biopsy-proven melanotic macule involving the fluorescence limited to lesion with no diascopy (Photo hard palate demonstrating irregular pigmentation and bor- courtesy: Professor Camile Farah, Perth Oral Medicine & der viewed with white light (a) and with optical fluores- Dental Sleep Centre, Perth, WA, Australia) cence imaging VELscope Vx (b) showing loss of

increase in number of melanocytes (Kaugars et al. 1993; Shen et al. 2011) (Fig. 6). Melanin may also be observed within melanophages or may be free (incontinence) in the subepithelial connective tissue, and these lesions do not typi- cally demonstrate elongated rete ridges (Alawi 2013).

Patient Management Oral/labial melanotic macules are considered benign lesions without malignant potential (Kauzman et al. 2004). Since early malignant melanoma may have a similar clinical appearance and exhibits a predilection for the maxillary alve- olar mucosa and palate, it is strongly advisable to perform an excisional biopsy for any suspected oral/labial melanotic macule for histopathologic analysis (Kauzman et al. 2004). Labial melanotic macules may be of cosmetic concern, and removal Fig. 6 Melanotic macule. Melanin pigmentation is noted in the basal epithelial layer (hematoxylin and eosin, 200Â) of these lesions may be accomplished by scalpel, cryosurgery, electrocautery, or laser ablation (Alawi 2013; Lim et al. 2014). are most commonly observed on the buccal mucosa, gingiva, and palate (Kauzman et al. 2004) (Figs. 2, 3, 4, and 5a, b). Intraoral lesions Oral Melanoacanthoma are often larger than those located on the lips (Meleti et al. 2008). Histopathological analysis Epidemiology of melanotic macules reveals an increase in mel- Oral melanoacanthoma represents a benign anin in the basal and parabasal layers of normal melanocytic lesion that is most commonly stratified squamous epithelium without an 6 E.T. Stoopler and F. Alawi

Clinical-Pathologic Features Oral melanoacanthoma typically presents as a diffuse, rapidly enlarging area of macular pig- mentation that may range in size from a few millimeters to several centimeters (Alawi 2013; Arava-Parastatidis et al. 2011) (Fig. 7). The lesion is typically brown to black in color with possible heterogeneity of color throughout the lesion. Oral melanoacanthoma usually manifests as a solitary lesion, but multifocal lesions have been reported (Arava-Parastatidis et al. 2011). Oral melanoacanthoma is most frequently observed Fig. 7 Oral melanoacanthoma affecting the buccal mucosa on the buccal mucosa followed by the palate, lips, gingiva, and tongue and may present unilat- erally or bilaterally (Alawi 2013; Arava- Parastatidis et al. 2011). This condition is primar- ily asymptomatic; however, some patients report burning sensations and/or pruritus associated with these lesions (Cantudo-Sanagustín et al. 2016). Histologically, oral melanoacanthoma is charac- terized by spongiotic epithelium containing den- dritic pigmented melanocytes throughout the lesional epithelium (Alawi 2013) (Fig. 8). A mild to moderate inflammatory infiltrate com- posed of lymphocytes and occasional eosinophils is observed in the underlying connective tissue (Alawi 2013).

Fig. 8 Dendritic (arrow) within the stratum Patient Management spinosum Treatment of oral melanoacanthoma is typically not indicated after diagnosis has been established. observed in dark-complexioned females between An incisional biopsy is necessary to rule out 30 and 50 years of age (Arava-Parastatidis et al. malignant melanoma as it is considered in the 2011). This condition has been reported in His- differential diagnosis of these lesions due to its panic, Asian, and Caucasian patients and has an ominous clinical presentation (Alawi 2013). overall female predilection (Arava-Parastatidis Spontaneous regression of oral melanoacanthoma et al. 2011). has been observed after biopsy, and recurrence of these lesions is rare (Alawi 2013; Arava- Etiology Parastatidis et al. 2011). Malignant transformation Oral melanoacanthoma is of unknown etiology of oral melanoacanthoma has not been reported (Gondak et al. 2012; Muller 2010). (Kauzman et al. 2004).

Pathophysiology The pathophysiologic mechanism for oral Melanocytic Nevus melanoacanthoma is most consistently associated with acute regional trauma or chronic irritation Epidemiology (Alawi 2013; Arava-Parastatidis et al. 2011). Melanocytic nevi, commonly referred to as “moles,” represent a group of benign tumors that Pigmented Lesions of the Oral Mucosa 7 develop due to melanocytic growth and prolifera- nevus), (2) migration of these cells into the mes- tion (Alawi 2013; Hatch 2005). Cutaneous nevi enchymal compartment (i.e., compound nevus), are common and typically develop during child- and (3) loss of the junctional component of the hood with most cutaneous lesions present before nevus so all remaining cells are located within the the age of 35 (Marangon Junior et al. 2015). In subepithelial compartment (intramucosal nevi) addition, Caucasians tend to develop cutaneous (Meleti et al. 2008). Blue nevi are melanocytic nevi more frequently than blacks or Asians lesions that typically appear slate blue to blue (Marangon Junior et al. 2015). The intramucosal black and account for up to 35% of all oral nevi nevus is the most frequently observed type of oral (Pinto et al. 2003). They are categorized into the nevus followed by the blue nevus, compound common type and the less frequently encountered nevus, junctional nevus, and combined nevus, in cellular type, and while each has specific charac- decreasing order of frequency (Alawi 2013). Oral teristic histopathologic features, both types harbor melanocytic nevi are frequently observed in the melanin particles deep to the surface so that third to fourth decades of life, and while the total reflected light appears blue to the observer (Pinto number of nevi tends to be higher in males, oral et al. 2003). Darkly pigmented blue nevi may be melanocytic nevi are more common in females clinically indistinguishable from other types of (Alawi 2013). melanocytic nevi.

Etiology Clinical-Pathologic Features In general, melanocytic nevi are acquired lesions Cutaneous junctional nevi commonly appear as a with both environmental and genetic factors sharply demarcated macule less than 6 mm in thought to play a role in the development of diameter with brown or blue coloration (Alawi cutaneous lesions (Alawi 2013; Muller 2010). 2013). Compound nevi may be macular or slightly Sun exposure is a well-recognized environmental elevated, soft with a relatively smooth surface, factor for development of cutaneous nevi (Lim while intradermal (cutaneous counterpart to et al. 2014). Recent studies have demonstrated intramucosal) nevi exhibits loss of pigmentation cutaneous nevi exhibiting somatic, activating and a papillomatous surface with possible central mutations in the BRAF, HRAS, and NRAS proto- hair growth (Alawi 2013). Oral melanocytic nevi oncogenes (Alawi 2013; Meleti et al. 2008). It have no distinguishing clinical characteristics; remains unclear if similar mutations are impli- however, they are usually asymptomatic, solitary, cated as the etiology of oral melanocytic nevi well circumscribed, less than 1 cm, macular or (Alawi 2013). nodular in appearance, and brown or blue in color (Alawi 2013) (Figs. 9 and 10). It is Pathophysiology The pathogenesis of melanocytic nevi, including oral melanocytic nevi, is poorly understood (Meleti et al. 2008). Acquired melanocytic nevi evolve through several developmental stages although not all nevi pass through each stage (Meleti et al. 2008). It has been postulated that junctional nevi evolve into compound nevi and ultimately into intramucosal nevi, with differenti- ating clinical and histologic features (Alawi 2013). Melanocytic proliferation can be consid- ered in three phases that correspond to each of the aforementioned nevi types: (1) proliferation of benign neoplastic melanocytes along the Fig. 9 Intramucosal nevus (arrow) located on the palate epithelial-mesenchymal junction (i.e., junctional (Courtesy of Dr. Edward Marcus) 8 E.T. Stoopler and F. Alawi

Fig. 10 Blue nevus (arrow) identified on the palate

Fig. 12 Intramucosal nevus composed of heavily pigmented nevus cells (hematoxylin and eosin, 200Â)

separated from the epithelial layer and found only in the connective tissue (Alawi 2013) (Figs. 11 Fig. 11 Intramucosal nevus. Nests of benign nevus cells and 12). The common blue nevus is characterized are identified within the lamina propria (hematoxylin and by an intramucosal proliferation of pigment- Â eosin, 200 ) laden, spindle-shaped melanocytes (Fig. 13), while the cellular blue nevus demonstrates sub- important to note that up to 15% of oral nevi may mucosal proliferation of both spindle-shaped and not exhibit any evidence of clinical pigmentation larger, round- or ovoid-shaped melanocytes (Pinto (Alawi 2013; Muller 2010). The most commonly et al. 2003). affected intraoral surfaces are the hard palate, buccal and labial mucosae, and gingiva, respec- Patient Management tively (Alawi 2013; Meleti et al. 2008). Treatment of cutaneous lesions are typically not Histopathologically, nevus cells confined to indicated unless a cosmetic concern exists and the basal layer at the junction of the epithelium there is a tendency for lesion regression with and connective tissue, especially at the tips of the advancing age (Alawi 2013). A biopsy is neces- rete ridges are characteristic of junctional nevi sary to confirm the diagnosis of oral melanocytic (Alawi 2013). As the junctional nevus evolves, nevi as the clinical presentation resembles other clustered melanocytes proliferate down into the focally pigmented lesions, such as malignant mel- connective tissue, forming nests of various sizes, anoma (Felix et al. 2013). Oral melanocytic nevi while some nevus cells are still seen at the are indicated for complete, conservative surgical epithelial-connective tissue surface, all of which excision with recurrence rarely reported (Felix are characteristic of the compound nevus (Alawi et al. 2013). The number of melanocytic nevi 2013). Intramucosal nevi demonstrate nevus cells represents an independent risk factor for Pigmented Lesions of the Oral Mucosa 9

varies depending on geographic regions with the highest rates of malignant melanoma occurring in New Zealand, Australia, and the United States (Jiang et al. 2015). It is estimated that 1 in 50 per- sons in the United States will be diagnosed with malignant melanoma during his or her lifetime (Lim et al. 2014). It accounts for approximately 4.6% of all new cancers and 1.7% of all cancer- related deaths in the United States (Gandhi and Kampp 2015). Incidence of malignant melanoma in European countries varies widely with approx- imately 2 to 20 cases diagnosed per 100,000 annually (Jiang et al. 2015). Malignant melanoma incidence in Asia, Africa, and Central and South America is considered low; however, the overall international incidence trends of malignant mela- suggest it is continuing to increase (Jiang et al. 2015). Median age of diagnosis is 64 years; however, incidence of malignant melanoma increases with age, reaching a peak between 80 and 84 years (Gandhi and Kampp 2015). Over- all, there is a male predilection for the condition, Fig. 13 Blue nevus. Spindle-shaped melanocytes but incidence is increasing in younger women of fi (arrows) are embedded within a densely brotic lamina child-bearing age (Lim et al. 2014). Prognosis of propria (hematoxylin and eosin, 200Â) malignant melanoma is dependent on depth of invasion, lesion thickness, and stage of disease at development of melanoma, with greater than diagnosis utilizing the Clark system, the Breslow 50 nevi increasing the risk of melanoma approx- classification, and the tumor node metastasis imately four- to fivefold (Lim et al. 2014). Over- (TNM) staging criteria, respectively (Lim et al. all, the risk of malignant transformation of 2014). Thicker lesions and advanced-stage dis- cutaneous nevi to melanoma is low, and current ease have a much lower 5-year survival rate, and evidence does not suggest that oral melanocytic metastatic melanoma is associated with a median nevi are markers for development of oral malig- survival time of 6 to 9 months (Lim et al. 2014). nant melanoma (Meleti et al. 2008). Oral malignant melanoma occurs much less frequently than its cutaneous counterpart; it com- prises less than 1% of all malignant in Malignant Melanoma the United States and 0.26% of all oral cavity cancers worldwide (Hashemi Pour 2008). Data Epidemiology suggests oral malignant melanoma may occur Malignant melanoma is a neoplasm of more frequently in certain countries, such as melanocytic origin with most cases occurring on Japan and Uganda, and dark-skinned races have the skin. While the incidence of malignant mela- a greater relative incidence of oral malignant mel- noma is lower compared to nonmelanoma skin anoma and higher mortality rate associated with cancers, it accounts for the vast majority of skin this condition (Tarakji et al. 2014). Generally, deaths (Lee et al. 2017). Malignant mela- malignant melanoma occurs at a slightly higher noma is most common among white populations frequency in males and generally presents after residing in Sunbelt regions of the world (Berwick 50 years of age with the peak age of diagnosis et al. 2016). International incidence of melanoma between 65 and 79 years (Alawi 2013; Femiano 10 E.T. Stoopler and F. Alawi et al. 2008). Unlike cutaneous malignant mela- fivefold (Lim et al. 2014). Sun protection at noma, histopathologic parameters cannot be reli- an early age may lower the subsequent risk of ably used to determine prognosis of oral malignant melanoma (Lim et al. 2014; MacLen- malignant melanoma (Alawi 2013). Oral malig- nan et al. 2003). nant melanoma is associated with a very poor The etiology of oral malignant melanoma is prognosis; 5-year survival rates range between unknown, and unlike its cutaneous counterpart, 5% and 50% with a large cluster at 10–25% risk factors for development have not been clearly (Femiano et al. 2008). Less than 10% of patients defined (Femiano et al. 2008). with distant metastases survive greater than 5 years, and the 10-year survival rate has been Pathophysiology reported to be 0% (Hashemi Pour 2008). Malignant melanomas may either develop de novo or from a preexisting benign melanocytic Etiology lesion (Chatzistefanou et al. 2016). Melanocytes While the cause of malignant melanoma has not are neuroectodermal derivatives and normally been clearly defined, multiple risk factors have migrate to the skin and other ectodermally derived been associated with onset of the cancer (Lim mucosae (Femiano et al. 2008). Less frequently, et al. 2014). melanocytes migrate to endodermally derived Exposure to the sun is the most important mucosae, such as those found in the head and environmental cause of cutaneous malignant mel- neck, and melanocytes have been observed in anoma, with ultraviolet radiation, primarily ultra- the deep stroma of oral mucosa (Femiano et al. violet A type, being most associated with 2008). Due to both extrinsic and intrinsic factors tumorigenesis and development of the disease previously described, proliferation of malignant (Lim et al. 2014). In light-skinned populations, melanocytes gives rise to a variety of melanoma the main nonsolar source of exposure to ultravio- types. let light are tanning beds, and several recent stud- ies demonstrate that the risk of malignant Clinical-Pathologic Features melanoma is increased by 20% for those who Malignant melanoma can have a variety of clini- ever used indoor tanning (Lim et al. 2014). cal appearances, with early lesions typically char- There is a relationship between a prior personal acterized by a macule or plaque with different or family history and malignant melanoma risk hues (brown, black, blue, red, or white) or occa- with approximately 10% of malignant melanomas sionally as an ulceration that does not heal (Lim occurring in familial clusters (Lim et al. 2014). et al. 2014). The ABCDE acronym (asymmetry, Mutations have been identified in two high- border irregularity, color variegation, diameter penetrance susceptibility genes, the cyclin- greater than 6 mm, and evolution or surface ele- dependent kinase inhibitor 2A (CDKN2A)on vation) is commonly used to initially evaluate chromosome 19p21 and cyclin-dependent kinase pigmented cutaneous lesions, although not all 4(CDK4) on chromosome 12q14 (Lim et al. malignant melanomas present with all of these 2014). The MC1R gene has been identified as a features (Lim et al. 2014). The anatomic distribu- low penetrance malignant melanoma susceptibil- tion of malignant melanoma differs by sex and ity gene, and alterations of the BRAF, HRAS, and age. In men, lesions are commonly located on the NRAS proto-oncogenes, and alteration or loss of trunk (55%), especially the back (39%), while in PTEN function, have been associated with malig- women, 42% of malignant melanoma lesions are nant melanoma development (Lim et al. 2014). localized to the lower extremities, with 24% on As discussed previously, the number of the lower leg (Lim et al. 2014). melanocytic nevi represents an independent risk Four major clinical-pathologic subtypes of factor for development of malignant melanoma, non-oral malignant melanoma have been with greater than 50 nevi increasing the risk described: superficial spreading melanoma, of malignant melanoma approximately four- to maligna melanoma, acral lentiginous Pigmented Lesions of the Oral Mucosa 11

Fig. 14 Superficial spreading melanoma of the scalp (1.2 mm in depth) in an 86-year-old male (Photo courtesy: Dr. Simon Lee, Head of Surgery, The Skin Hospital, Fig. 16 Nodular melanoma on the toe (5.7 mm in depth) Darlinghurst, NSW, Australia) in a 67-year-old male (Photo courtesy: Dr. Simon Lee, Head of Surgery, The Skin Hospital, Darlinghurst, NSW, Australia)

a superficial spreading melanoma appears varie- gated with a sharply marginated, irregular border and is typically smaller than 3 cm (Lim et al. 2014). Multiple hues and shades are often noted with superficial spreading melanoma, such as tan, brown, gray, black, blue, white, and pink (Lim et al. 2014) (Figs. 14 and 15). Nodular melanoma represents 15% of cutaneous melanomas and is more common in men (Lim et al. 2014). Typically, they are found on the trunk, and, interestingly, one-third of lesions develop in the head and neck (Lim et al. 2014). Clinically, nodular melanoma may be deeply pigmented (Fig. 16); however, due to the possibility of melanoma cells being so poorly differentiated, these cells may stop produc- ing melanin, resulting in a nonpigmented amelanotic macule. melanoma accounts for 5–10% of melanomas and has a predilection for sun-exposed areas such as the nose, malar region, temple, forehead, neck, and forearms in older adults (Lim et al. 2014). It pre- Fig. 15 Superficial spreading melanoma of the cheek sents as a slowly enlarging, asymmetric macule (0.7 mm in depth) in a 71-year-old male (Photo courtesy: with irregular borders that is variably pigmented Dr. Simon Lee, Head of Surgery, The Skin Hospital, Darlinghurst, NSW, Australia) with tan, brown, black, and possibly white colors (Lim et al. 2014). Acral lentiginous melanoma, the least common subtype, accounts for less than melanoma, and nodular melanoma (Lim et al. 5% of all melanomas but accounts for 70% of 2014). Superficial spreading melanoma is the melanomas seen in African-Americans (Lim most common subtype, accounting for 70% of et al. 2014). Clinically, it affects hairless areas all melanoma diagnoses (Lim et al. 2014). Most like subungual, palmar, and plantar regions and lesions of this type occur de novo, and, clinically, 12 E.T. Stoopler and F. Alawi

along the basal layer of the surface epithelium prior to invasion of the underlying connective tissue, which is described as radial extension (Lim et al. 2014). Pagetoid and nested epithelioid melanocytes cells in the intraepidermal portion with poor circumscription are characteristic of superficial spreading melanoma (Lim et al. 2014). In contrast, nodular melanoma is charac- terized by vertical growth of malignant melano- cytes into the connective tissue, which typically occurs early in the disease process. The tumor usually appears as pleomorphic, spindle-shaped, Fig. 17 Malignant melanoma present on the lower labial mucosa or epithelioid cells arranged in loosely aggregated sheets and cords. Oral malignant melanomas are usually charac- mucous membranes and presents as a variably terized by sheets or islands of malignant melano- colored macule, usually brown or black, which cytes within the connective tissue with possible develops irregular borders and increases in size pagetoid spread (Alawi 2013; Chatzistefanou over time (Lim et al. 2014). et al. 2016) (Fig. 19). Poorly differentiated tumors Oral malignant melanoma, however, has no may exhibit only minimal pigment or none at all such distinctive clinical appearance and is often (Fig. 20). Like its cutaneous counterpart, oral initially asymptomatic. The lesion typically malignant melanomas exhibit an initial radial begins as a brown to black macule with irregular growth phase, typically followed by a vertical borders and may even lack pigment (Hashemi pattern of growth with deeper tissue invasion Pour 2008)(Fig.17). Lesions are relatively soft (Chatzistefanou et al. 2016). The presence of to palpation and may be accompanied by ery- malignant cells in the lamina propria and a high thema and/or ulceration, which can potentially tumor mitotic rate are characteristic of invading cause pain (Mohan et al. 2013). Tooth mobility activity (Chatzistefanou et al. 2016). Immunohis- or spontaneous exfoliation, root resorption, anes- tochemistry studies using antibodies directed thesia/paresthesia, and bone loss may be evident against HMB45, S100, MART1, and/or micro- (Mohan et al. 2013). Diffuse, contiguous muco- phthalmia-associated transcription factor (MitF) sal pigmentation should be viewed suspiciously are necessary for definitive diagnosis of oral as possible malignant melanoma compared to malignant melanoma (Muller 2010) (Fig. 21). diffuse, noncontiguous pigmentation (Alawi 2013). While any mucosal site may be affected, Patient Management the palate is the most common intraoral location Biopsy is mandatory for any persistent solitary of oral malignant melanoma followed by the pigmented lesion, as they can be representative maxillary gingiva/alveolar crest (Femiano et al. of a variety of processes, from innocuous lesions 2008)(Fig.18a, b). There may be radiographic to life-threatening malignant melanoma (Mohan evidence of “moth-eaten” or irregular bone et al. 2013). Once malignant melanoma is diag- destruction associated with these lesions, and nosed, it is important, yet challenging, to deter- cervical lymph nodes may be palpable due to mine if the lesion represents a primary malignancy metastasis at initial presentation (Hashemi Pour or a metastasis from a distant site, as this informa- 2008). tion will dictate tumor staging and direct therapy Microscopically, superficial spreading mela- (Alawi 2013). Surgical excision is the primary noma, lentigo maligna melanoma, and acral treatment modality for malignant melanoma, lentiginous melanoma demonstrate a lateral and which is curative for most patients with early- superficial spread of melanocytic tumor cells Pigmented Lesions of the Oral Mucosa 13

Fig. 18 Biopsy-proven gingival malignant melanoma in malignant cells and superficial underlying connective tis- 67-year-old male appearing as multiple black pigmented sue (b) (Photo courtesy: Professor Camile Farah, Oral lesions along the attached gingiva adjacent to upper ante- Health Centre of Western Australia, School of , rior teeth (a). Hematoxylin- and eosin-stained histological University of Western Australia, Perth, WA, Australia) section of lesion demonstrating brown pigment in stage lesions (Chatzistefanou et al. 2016). Wide excision is recommended, but the recommended Multifocal/Diffuse Pigmentation surgical margin varies, depending on the depth of the tumor (Lim et al. 2014). Lymph node dissec- Physiologic Pigmentation tion is typically performed on patients with clini- cally evident regional metastasis in the absence of Epidemiology “ ” distant metastasis (Chatzistefanou et al. 2016). Physiologic ( racial ) pigmentation is the most Adjuvant systemic therapies have limited success common multifocal or diffuse oral mucosal pig- in the treatment of advanced-stage malignant mel- mentation; however, it is not directly related anoma, which include interferon-a, high-dose to skin color (Gaeta et al. 2002; Tarakji et al. interleukin 2, ipilimumab (a monoclonal antibody 2014). It is typically observed in dark-skinned that works to activate the immune system individuals, most commonly in African, Asian, by targeting CTLA-4, a protein receptor that or Mediterranean populations without gender pre- downregulates the immune system), and dilection (Kauzman et al. 2004; Meleti et al. fi bevacizumab (a recombinant humanized mono- 2008). It is seen during the rst two decades of clonal antibody that blocks angiogenesis by life but may not be observed and/or of individual inhibiting vascular endothelial growth factor-A) concern until later in life (Kauzman et al. 2004; (Lim et al. 2014). The role of radiotherapy is Tarakji et al. 2014). limited since malignant melanoma is radio resis- tant compared with other cancers (Lim et al. Etiology 2014). The etiology of physiologic pigmentation has not been identified (Muller 2010). 14 E.T. Stoopler and F. Alawi

Fig. 21 Anti-HMB45 immunohistochemical analysis. The malignant tumor cells (see Fig. 6) were strongly reac- tive with the melanocytic marker HMB45

intensity of the lesions may be influenced by hormones, smoking, and systemic medications (Muller 2010).

Clinical-Pathologic Features Fig. 19 . Sheets and cords of malig- Physiologic pigmentation typically affects the nant melanocytes scattered throughout the lamina propria gingiva, where it presents as a bilateral, well- Â (hematoxylin and eosin, 100 ) demarcated, ribbon-like band of brown pigment that usually does not affect the marginal gingiva nor interfere with normal tissue architecture (Kauzman et al. 2004; Tarakji et al. 2014) (Figs. 22 and 23). Other sites that may be affected include the buccal mucosa, lips, palate, and tongue (Kauzman et al. 2004). The color associ- ated with this condition ranges from light brown to black, and patients affected by physiologic pigmentation are asymptomatic (Muller 2010; Tarakji et al. 2014). Microscopically, this condi- tion is characterized by the presence of increased amounts of melanin deposition within the basal cell layer (Gondak et al. 2012) (Fig. 24).

Patient Management Fig. 20 Amelanotic melanoma exhibiting only focal pig- mentation (arrow). The tumor cells are poorly differenti- Diagnosis of physiologic pigmentation is typi- ated (hematoxylin and eosin, 200Â) cally made based on clinical appearance, and treatment is not indicated for this condition Pathophysiology (Meleti et al. 2008). Biopsy may be indicated if The increased pigmentation associated with this pigmentation is of recent onset in adulthood condition is attributed to increased melanocytic and/or the patient reports physical symptoms that activity rather than an increase in numbers may be related to a systemic disorder, such as of melanocytes. It has been reported that color Addison disease, that may cause development of Pigmented Lesions of the Oral Mucosa 15

Fig. 22 Physiologic pigmentation of the maxillary and mandibular gingiva

Fig. 24 Physiologic pigmentation. Anti-MART1 anti- body was used to highlight normal melanocytes (arrows) residing in the basal epithelial layer Fig. 23 Physiological pigmentation in a patient of African heritage appearing as widespread brown and black pig- mentation along the attached gingiva (Photo courtesy: Pro- fessor Camile Farah, Perth Oral Medicine & Dental Sleep Drug-Induced Melanosis Centre, Perth, WA, Australia) Epidemiology (Muller 2010). This condition Mucosal coloration can be induced by an array of – may be of esthetic concern to patients, and medications. It has been estimated that 10 20% of although procedures such as gingivectomy, laser all cases of acquired melanocytic pigmentation therapy, and cryotherapy have been used to may be induced by drugs (Dereure 2001). remove affected tissues, these lesions may even- tually recur. The practice of gingival tattooing in Etiology females is a custom that is practiced among sev- Several medications have been implicated in eral African ethnic groups and may appear clini- drug-induced melanosis such as hormones and cally similar to physiologic pigmentation (Rawal oral contraceptives; antipsychotics including et al. 2007). Traditionally, products such as lan- chlorpromazine; antimalarial drugs such as tern soot and botanical resins are applied to the hydroxychloroquine and quinacrine; chemothera- fl maxillary labial gingiva of preteen and teenaged peutic agents including bleomycin, busulfan, uo- females via needles and thorns to the affected rouracil, and imatinib; anti-retroviral agents surfaces (Brooks and Reynolds 2007, Rawal including zidovudine; anti-fungal drugs such as et al. 2007.) This practice is primarily for cosmetic ketoconazole; and anti-microbial agents including reasons to make the teeth appear whiter, which is a minocycline and tetracycline (Moraes et al. 2011; highly desirable beauty mark in some African Alawi 2013; Yuan and Woo 2015). societies (Rawal et al. 2007) (Fig. 25). 16 E.T. Stoopler and F. Alawi

Fig. 25 Extensive gray/black coloration of the maxillary labial attached gingiva as a result of intraoral cosmetic Fig. 26 Chemotherapy-induced pigmentation affecting tattooing. Note the presence of diffuse brown pigmentation the tongue involving the mandibular labial gingiva and the anterior portions of the maxillary labial gingiva consistent with physiological pigmentation (Photo courtesy: Professor of melanocytes are characteristics of drug- Michael McCullough, Melbourne Dental School, Univer- induced melanotic lesions. sity of Melbourne, VIC, Australia) Patient Management Diagnosis of drug-induced melanosis can be Pathophysiology achieved if a temporal association is made In some cases, the coloration is true pigmentation between the use of a medication and development resulting from stimulation of melanin synthesis by of pigmentation (Alawi 2013). Biopsy is the drug and/or its metabolites; the mechanisms warranted if a diagnosis of drug-induced may differ between different drugs. In other cases, melanosis cannot be appropriately rendered drug precipitates deposit within the lamina propria (Alawi 2013). Drug-induced melanosis is clini- or submucosa resulting in blue-brown-black cally inconsequential beyond potential esthetic mucosal coloration (Alawi 2013; Yuan and Woo concerns. Discontinuation of the medication 2015). may eventually resolve the pigmentation, which may take weeks to months to achieve (Alawi Clinical-Pathologic Features 2013). Malignant transformation of drug-induced Drug-induced pigmentation can affect any melanotic lesions has not been reported (Tarakji mucosal site. In general, the gingiva, tongue, et al. 2014). and hard palate are most commonly affected (Fig. 26). Some medications, such as hydroxychloroquine, produce characteristic pat- Smoker’s Melanosis terns of mucosal pigmentation; the palate is usu- ally affected in patients taking this drug (Alawi Epidemiology 2013). Minocycline can induce true melanocytic Smoker’s melanosis is the term used to describe pigmentation and produce precipitates that oral mucosal pigmentation that develops second- deposit within soft and hard tissues, including ary to heavy tobacco use. This condition has been bone, and appear blue gray or even green in reported to affect nearly 22% of smokers and is color (Hatch 2005; Kauzman et al. 2004; more common in females (Kauzman et al. 2004; Bowen and McCalmont 2007; Tarakji et al. Muller 2010). This condition may cause oral pig- 2014;YuanandWoo2015). Microscopically, mentation to develop in light-skinned individuals basilar hyperpigmentation and melanin inconti- and accentuate pigmentation in dark-skinned indi- nence without a concomitant increase in number viduals (Tarakji et al. 2014). Pigmented Lesions of the Oral Mucosa 17

Etiology Polycyclic amines, such as nicotine and benzopy- rene, are chemical compounds in tobacco smoke that have demonstrated the ability to stim- ulate melanocytes to produce melanin (Hassona et al. 2016).

Pathophysiology Melanin pigmentation in the skin is protective against ultraviolet damage, and melanocytes in non-sun-exposed areas produce melanin that can bind to noxious substances (Meleti et al. 2008). It has been postulated that melanin produc- tion stimulated by tobacco smoke may have a protective role against the harmful agents in the smoke, such as those described previously (Hassona et al. 2016; Muller 2010). Additionally, the heat of the smoke is thought to be a stimulating factor for pigment development (Alawi 2013). Since smoker’s melanosis is more prevalent in women, it has been suggested that female sex hormones (i.e., estrogen) may have a role in development of this condition (Kauzman et al. Fig. 27 Smokers’ melanosis appearing as diffuse faint 2004; Muller 2010). brown pigmentation on the buccal mucosa (Photo cour- tesy: Professor Camile Farah, Perth Oral Medicine & Den- tal Sleep Centre, Perth, WA, Australia) Clinical-Pathologic Features Smoker’s melanosis typically presents as diffuse, patchy melanosis affecting the anterior vestibular correlated with characteristic physical findings on maxillary and mandibular gingivae, buccal clinical examination. If the lesion is present in an mucosa, labial commissures, lateral tongue, pal- unexpected location and/or unusual changes are ate, and/or floor of the mouth (Muller 2010) observed, such as surface elevation and/or (Fig. 27). The color of the lesions is typically increased melanin deposition, biopsy should be brown to black (Alawi 2013). The areas of pig- considered (Kauzman et al. 2004). If only one mentation dramatically increase during the first mucosal site is affected, melanoma should be year of smoking and often correlate to the number considered in the differential diagnosis as it can of cigarettes smoked per day (Kauzman et al. also present as diffuse patchy pigmentation, and 2004). Histopathologically, this condition is char- tissue biopsy is warranted (Alawi 2013). Other acterized by increased melanin pigmentation of causes of diffuse melanin pigmentation, such as the basal cell layer of the surface epithelium with those described elsewhere in this chapter, should collections of incontinent melanin pigmentation be excluded. Cessation of smoking habits results within the superficial connective tissue and in in gradual resolution of the lesions attributed to scattered macrophages (Alawi 2013). smoker’s melanosis, typically within a 3-year period (Kauzman et al. 2004; Tarakji et al. Patient Management 2014). No additional treatment is recommended Diagnosis of smoker’s melanosis is usually as smoker’s melanosis is not considered a pre- established by a positive history of tobacco use neoplastic condition (Alawi 2013). 18 E.T. Stoopler and F. Alawi

Post-inflammatory (Inflammatory) Hyperpigmentation

Epidemiology Post-inflammatory (inflammatory) hyper- pigmentation is a condition characterized by pig- ment deposition in area(s) subjected to inflammation or previous injury that is more com- monly observed in dark-complexioned individ- uals (Alawi 2013).

Etiology The etiology of post-inflammatory (inflamma- tory) hyperpigmentation has not been determined (Gondak et al. 2012; Tarakji et al. 2014). Fig. 28 Post-inflammatory (inflammatory) pigmentation associated with lichenoid lesions on the buccal mucosa Pathophysiology Inflammatory conditions, such as , cause perturbation of epithelial melanocytes, resulting in increased melanin deposition in affected areas (Kauzman et al. 2004).

Clinical-Pathologic Features This condition is characterized by diffuse patches of brown to black pigmentation of the involved mucosa in the area of the underlying inflammatory condition (Kauzman et al. 2004) (Figs. 28 and 29). Intraorally, these lesions are most often associated with lichenoid inflammation, while skin lesions attributed to post-inflammatory (inflammatory) hyperpigmentation commonly result from previ- ous trauma (Alawi 2013). In rare cases, the pig- mentation may be so dark that it clinically obscures the underlying lichenoid condition (Alawi 2013). Histopathologic features of this condition include increased melanin pigment within basal cells and melanin incontinence accompanied by typical lichenoid histologic fea- tures (Alawi 2013).

Patient Management Fig. 29 Post-inflammatory pigmentation on the left buc- Treatment is directed toward managing the under- cal mucosa in a patient with mild oral lichen planus (Photo lying inflammatory condition when symptomatic, courtesy: Professor Camile Farah, Perth Oral Medicine & typically with topical corticosteroids. Pigmenta- Dental Sleep Centre, Perth, WA, Australia) tion may or may not resolve with resolution of the lichenoid inflammation, and if it does, it may take several months to fade (Alawi 2013). Pigmented Lesions of the Oral Mucosa 19

Laugier-Hunziker Pigmentation surfaces, such as the facial skin and abdomen, and other mucosal surfaces, including the esoph- Epidemiology agus, conjunctiva, and anogenital mucosa (Alawi Laugier-Hunziker pigmentation (Laugier-Hunziker 2013; Nikitakis and Koumaki 2013). Typical his- syndrome, Laugier-Hunziker-Baran syndrome) is tologic findings associated with Laugier-Hunziker characterized by acquired melanotic pigmentation pigmentation include increased basal keratinocyte of the labial and buccal mucosa (Alawi 2013; Yago melanin without an increase in number of mela- et al. 2008). This is considered a rare condition that nocytes, melanin incontinence, and epithelial usually begins in the third to fifth decade of life acanthosis in the absence of rete ridges or inflam- with an overall female-male ratio of 2:1 (Nikitakis mation (Nikitakis and Koumaki 2013). and Koumaki 2013;Yagoetal.2008). This condi- tion has been reported in individuals in North Patient Management America, Europe, and Asia and has been more Treatment for this condition is typically not indi- commonly observed in Caucasian or light-skinned cated unless there is an esthetic and/or psycholog- individuals (Yago et al. 2008). ical concern (Nikitakis and Koumaki 2013). Laser therapy and cryotherapy have been used to remove Etiology pigmentation, but recurrence is possible (Nikitakis While the etiology of Laugier-Hunziker pigmen- and Koumaki 2013). It is important to consider tation is unknown, hormonal or genetic roles have systemic etiologies in the differential diagnosis of not been associated with this condition (Alawi Laugier-Hunziker pigmentation, such as Addison 2013; Fernandes et al. 2015; Nikitakis and disease and Peutz-Jeghers syndrome, as these con- Koumaki 2013). ditions are also characterized by multiple oral mucosal macules (Nikitakis and Koumaki 2013). Pathophysiology A thorough medical, social, and family history, in The precise pathophysiologic mechanism of addition to a complete review of systems, are Laugier-Hunziker pigmentation is unclear, but it important in rendering an accurate diagnosis and is considered an acquired appropriate referral to medical specialists, if neces- that results from increased basal keratinocyte mel- sary. Biopsy may be considered to confirm the anin without an increase in melanocytes clinical diagnosis and rule out other sources of (Nikitakis and Koumaki 2013). oral pigmentation. Laugier-Hunziker pigmentation is a diagnosis of exclusion after all other potential Clinical-Pathologic Features sources for pigmentation have been eliminated as Multifocal, macular hyperpigmentation of the oral an etiology for the condition (Alawi 2013). mucosa and lips is characteristic of Laugier- Laugier-Hunziker pigmentation is not associated Hunziker pigmentation (Alawi 2013; Nikitakis with malignant predisposition (Fernandes et al. and Koumaki 2013). Lesions may be solitary or 2015; Rangwala et al. 2010;Yagoetal.2008). confluent, brown to black to gray in color, and have been reported in all regions of the oral cavity, including the lips, buccal mucosa, tongue, hard Pigmentation Associated palate, and gingiva (Nikitakis and Koumaki with Systemic or Genetic Disorders 2013). Melanotic longitudinal streaks in the nails without associated nail dystrophy are frequently Adrenal Insufficiency (Addison associated with oral pigmentation (Alawi 2013; Disease) Nikitakis and Koumaki 2013; Yago et al. 2008). Up to 60% of affected patients have nail involve- Epidemiology ment with fingernails more commonly affected Adrenal insufficiency is a potentially life- than toenails (Fernandes et al. 2015). Similar threatening endocrinopathy that is characterized lesions may be observed on other cutaneous by diminished production of glucocorticoids 20 E.T. Stoopler and F. Alawi

(cortisol) with or without a concomitant defi- through an intricate negative feedback mecha- ciency in mineralocorticoid and adrenal androgen nism. When reduced cortisol levels are sensed levels (Naziat and Grossman 2000). Dysfunction by the hypothalamus, the CRH-POMC-ACTH- in the hypothalamus-pituitary-adrenal gland axis cortisol signaling cascade is reactivated. gives rise to adrenal insufficiency. Primary, sec- OMH is observed only in primary adrenal ondary, and tertiary forms of adrenal insufficiency insufficiency (Charmandari et al. 2014). The con- are dependent upon the anatomic site of origin stitutively low cortisol levels stimulate persistent precipitating the dysfunction. POMC production to yield high levels of ACTH. An estimated 4.4–6 new cases of primary adre- Since the defective adrenal glands are unable to nal insufficiency develop per million people per sufficiently respond to ACTH, the signaling cas- year (Charmandari et al. 2014). In contrast, sec- cade remains active. In conjunction with ACTH ondary adrenal insufficiency is more common overproduction, α-MSH levels are also increased than the primary disease with an estimated preva- in parallel. α-MSH is a short peptide encoded lence of 150–280 per million people. Overall, the within the ACTH peptide and generated via post- prevalence of Addison disease in Caucasians is translational cleavage (Anderson et al. 2016). estimated to be between 1 in 8000–20,000 in the Since α-MSH is a potent stimulator of melano- United States and Europe (Naziat and Grossman genesis, this triggers the mucocutaneous pigmen- 2000). Primary adrenal insufficiency manifests tation observed in primary adrenal insufficiency more frequently in females than males and often (Anderson et al. 2016; Feller et al. 2014b). ACTH between the ages of 30 and 50. Secondary disease and α-MSH levels are reduced in secondary and is also more common in females but is usually tertiary adrenal insufficiency (Charmandari et al. diagnosed later in life. While the prevalence of 2014). Thus, the pigmentation does not occur in oral mucosal hyperpigmentation (OMH) associ- these forms of the disease. ated with adrenal insufficiency is not known, OMH is observed only in primary disease states. Pathophysiology Primary adrenal insufficiency is caused by adre- Etiology nocortical disease. While the most common cause The hypothalamus-pituitary-adrenal gland axis is autoimmune adrenalitis, other conditions such is tightly coordinated to ensure glucocorticoid as cancer, infection, and hemorrhagic infarction homeostasis (Charmandari et al. 2014). The can also directly damage the adrenal glands hypothalamus produces corticotropin-releasing (Charmandari et al. 2014). Several genetic disor- hormone (CRH) and vasopressin. These hor- ders may lead to congenital defects in adrenal mones act synergistically on the pituitary gland gland structure and function. Other genetic dis- to activate pro-opiomelanocortin (POMC) gene eases may affect sensitivity of the glands to expression (Anderson et al. 2016). The ACTH, limit glucocorticoid synthesis, or acceler- corresponding 241 amino acid POMC polypep- ate cortisol metabolism. A number of medications tide then undergoes an array of posttranslational can also limit glucocorticoid biosynthesis or modifications to yield several biologically distinct accelerate cortisol metabolism (Michels and hormone peptides. These include adrenocortico- Michels 2014). Examples include phenobarbital tropic hormone (ACTH); α-, β-, and and phenytoin which activate cytochrome P450 γ-melanotropins (also known as melanocyte stim- enzymes thereby stimulating glucocorticoid ulating hormone), respectively, β- and metabolism. The antimycotic fluconazole and γ-lipotropins; β-endorphin; and metenkephalin ketoconazole reduce cortisol synthesis by (Anderson et al. 2016). ACTH is secreted into inhibiting mitochondrial cytochrome P450 the circulation and binds to receptors in the adre- enzymes. In rare instances, the use of the tyrosine nal cortex to stimulate glucocorticoid production kinase inhibitors imatinib, saracatinib, and and release. Once serum cortisol levels are stabi- sunitinib has been associated with adrenal insuf- lized, ACTH and CRH synthesis are inhibited ficiency and other endocrinopathies, including Pigmented Lesions of the Oral Mucosa 21

Patient Management Treatment of adrenal insufficiency should be implemented as soon as a deficiency state is rec- ognized. Glucocorticoid replacement therapy via oral hydrocortisone supplementation (15–25 mg daily divided in two or three doses) is usually the treatment of choice (Napier and Pearce 2014). The exact daily dosage should be titrated based on the patient’s weight; higher dosing is typically recommended for heavier patients. Low-dose oral prednisone therapy (3–5 mg once daily) or intramuscular dexamethasone (0.5 mg once daily) can also be used. Dexamethasone injections are Fig. 30 Oral mucosal pigmentation in a Caucasian patient recommended for patients who are unable to tol- with adrenal insufficiency. Melanin pigmentation is noted in the basal epithelial layer. This patient was diagnosed erate oral medications. Mineralocorticoid- and with Addison disease 2 months after he developed diffuse androgen-replacement therapy is also frequently oral pigmentation and histopathologic evaluation of the necessary. Once serum cortisol levels normalize, biopsy tissue (hematoxylin and eosin, 200Â) the pigmentation may eventually resolve. hypothyroidism and alterations of glucose metab- Cushing Disease olism (Lodish 2013). Secondary insufficiency is caused by surgical Cushing syndrome is a potentially life- trauma and neoplastic (e.g., pituitary adenoma) or threatening disease caused by prolonged exposure genetic disorders (e.g., Prader-Willi syndrome) to hypercortisolism that may arise from exoge- affecting the anterior lobe of the pituitary gland nous or endogenous causes (Sharma et al. 2015). resulting in reduced secretion of ACTH Overadministration of glucocorticoids such as (Charmandari et al. 2014). Tertiary adrenal insuf- dexamethasone and prednisone, or drugs that ficiency is usually caused by chronic exposure to reduce the clearance of synthetic glucocorticoids, exogenous glucocorticoids resulting in decreased including itraconazole, are the major cause of secretion of CRH and/or vasopressin from the Cushing syndrome. Endogenous Cushing syn- hypothalamus. drome is classified into ACTH-dependent and ACTH-independent variants (Lacroix et al. Clinical-Pathologic Features 2015). The onset of primary adrenal insufficiency may Cushing disease is the most common cause of be insidious and nonspecific. The first sign of ACTH-dependent endogenous Cushing syn- disease may be diffuse bronzing of the skin drome (Sharma et al. 2015). Cushing disease is with or without patchy OMH (Fig. 30). With primarily induced by an ACTH-secreting pitui- persistence of the cortisol deficiency, the clinical tary adenoma. Other ACTH-dependent forms of signs and symptoms may become generalized. Cushing syndrome may arise from ectopic Complications may include weakness and ACTH- or, rarely, CRH-secreting tumors origi- fatigue, gastrointestinal complaints, orthostatic nating in other anatomic sites. ACTH- hypotension, musculoskeletal pain, anorexia, independent Cushing syndrome develops sec- salt craving, and behavioral changes ondary to functional adrenal neoplasms (Lacroix (Charmandari et al. 2014). While the hyper- et al. 2015). Oral melanocytic pigmentation only pigmentation is not clinically significant, its sud- develops in ACTH-dependent Cushing syn- den appearance may necessitate evaluation of the drome. The ensuing discussion will focus on patient for Addison disease. Cushing disease. 22 E.T. Stoopler and F. Alawi

Epidemiology Pathophysiology The estimated incidence rate of endogenous Excessive and pathologically constitutive secre- Cushing syndrome is 0.7–2.4 per million tion of ACTH results in persistent stimulation of populations per year, with a standardized mortal- the adrenal glands to release cortisol (Lonser et al. ity ratio of almost four (Sharma et al. 2015). It is 2016). Since the pituitary neoplasm is resistant to possible that incidence rates of endogenous Cush- the negative feedback control mechanisms, ing syndrome are underestimated. Studies of ACTH and cortisol levels remain high. The muco- patients with uncontrolled diabetes, hypertension, cutaneous pigmentation develops via the same or early-onset osteoporosis have revealed previ- mechanism as that described for primary adrenal ously undiagnosed Cushing syndrome in a subset insufficiency, i.e., α-MSH levels increase in par- of cases (De Leo et al. 2012). allel with ACTH. Most patients die of disease within the first In rare instances, Cushing disease may also be year after initial presentation. Even with appropri- a manifestation of genetic diseases, including ate treatment, the risk for disease-related morbid- multiple endocrine neoplasia type 1 (MEN1) and ity and mortality remains significantly higher than multiple endocrine neoplasia type 4 (MEN4) that of the general population and may persist for (Schernthaner-Reiter et al. 2016). Germline muta- several years after normalization of cortisol levels tions of the MEN1 and CDKN1B genes precipi- (Lonser et al. 2016). In particular, treated patients tate MEN1 and MEN4 syndromes, respectively may retain a high risk for future development of (Schernthaner-Reiter et al. 2016). diabetes, dyslipidemia, obesity, and Germline mutations in the aryl-hydrocarbon neurocognitive and psychiatric disorders. Risk receptor-interacting protein predispose to pitui- from death associated with cardiovascular com- tary adenomas (pituitary adenoma predisposition plications also remains elevated. syndrome) (Lloyd and Grossman 2014). Cushing Cushing disease accounts for 65–80% of all disease may also manifest in Carney complex ACTH-dependent forms of Cushing syndrome resulting from pituitary adenoma harboring a (Lacroix et al. 2015). It has an estimated preva- germline mutation in PRKAR1A (Schernthaner- lence of 39.1 per million persons. Overall, females Reiter et al. 2016). Similarly, somatic mutations are more commonly afflicted than males; ratios of of GNAS (G-protein-coupled receptor alpha sub- 3–5:1 have been reported. Although Cushing dis- unit [Gsα], which activates adenylate cyclase) ease can present at any age, most cases are diag- also predispose to pituitary adenomas (Brown nosed in the fourth decade, with females et al. 2010). GNAS mutations are associated with frequently being diagnosed at an earlier age than McCune-Albright syndrome. Patients with this males. disorder also develop pigmented macular lesions of the skin known as café-au-lait spots. Caf- Etiology é-au-lait pigmentation does not occur within the Cushing disease is usually caused by a primary oral cavity. pituitary pathology – usually an ACTH-secreting adenoma (Lonser et al. 2016). In rare instances, Clinical-Pathologic Features tumors in other anatomic sites can also precipi- Oral mucosal and/or cutaneous hyper- tate ACTH-dependent ectopic Cushing syn- pigmentation may be one of the earliest signs of drome. These include small cell neuroendocrine Cushing disease (Lacroix et al. 2015) (Fig. 31). and carcinoid tumors of the lung and other More significantly, prolonged exposure to hyper- organs, islet-cell tumors of the pancreas, medul- cortisolism results in an array of variably severe lary thyroid carcinoma, pheochromocytomas, and potentially life-threatening complications. and thymomas. Hyperpigmentation may be Most commonly these include but are not limited observed in any ACTH-dependent form of Cush- to obesity, diabetes mellitus, moon facies, hyper- ing syndrome. tension, amenorrhea, osteoporosis, hirsutism, abdominal striae, dorsocervical fat pads (“buffalo Pigmented Lesions of the Oral Mucosa 23

Human Immunodeficiency Virus (HIV): Associated Pigmentation

Epidemiology OMH is a recognized occurrence in HIV-seropos- itive and AIDS-afflicted individuals. If it develops, the pigmentation usually becomes apparent within the first 2 years after initial HIV diagnosis and usually in patients with CD4+ T-cell counts of 200 cells/mm3 or less (Feller et al. 2014a). A potential relationship between viral load and OMH remains uncertain. Fig. 31 Multifocal mucosal pigmentation on the hard palate (arrows) in a patient who was eventually diagnosed The overall prevalence of OMH is not known. with Cushing syndrome However, there are geographic and ethnic differ- ences that could reflect specific characteristics of the HIV infection, access to appropriate treatment, hump”), cutaneous purpura, poor wound healing, and/or administration of specific drug regimens. muscular weakness, psychological, psychiatric In South Africa, Venezuela, and India, 18.5–38% and neurocognitive disturbances, immune sup- of HIV-seropositive patients were identified with pression, male impotence, and female infertility OMH (Bravo et al. 2006; Chandran et al. 2016; (Lacroix et al. 2015). Feller et al. 2014a). In contrast, in Greece and Italy OMH accounts for less than 2% and 7%, respec- Patient Management tively, of all examined patients. In general, muco- There is no specific treatment for the pigmenta- sal pigmentation is usually more prominent in tion. Treatment of the underlying cause of Cush- darker-skinned individuals and may be more ing disease – usually surgical removal of the prevalent in females than in males (Feller et al. pituitary tumor – often times has an immediate 2014a). In at least one study, HIV-associated inhibitory effect on cortisol secretion (Lau et al. OMH was also significantly associated with 2015). In cases where the tumor may be inopera- smoking (Chandran et al. 2016). ble, radiation therapy may be employed, or the hypercortisolism may be treated medicinally. Etiology Medical therapies can target the pituitary gland, The etiology of HIV/AIDS-associated pigmenta- the adrenal gland, or the peripheral tissues. Pitui- tion is multifactorial. There is currently no evi- tary targeting is designed to inhibit ACTH syn- dence HIV can directly infect or activate thesis and secretion. Cabergoline (dopamine melanocytes (Feller et al. 2014a). Instead, 2 receptor agonist) and pasireotide (somatostatin HIV-induced cytokine dysregulation may induce 5 receptor agonist) are two drugs that are currently OMH. Nonspecific, generalized oral mucosal available for patients who are poor surgical can- inflammation could also be contributory. didates or who failed surgical therapy (Lau et al. Pro-inflammatory cytokines including interleukin 2015). Steroidogenic inhibitors including ketoco- (IL)-1, IL-6, and tumor necrosis factor (TNF)-α nazole may be used to inhibit cortisol synthesis. are known to regulate melanocytes and Mifepristone is a progesterone receptor antagonist melanogenesis (Feller et al. 2014b). Constitutive that also inhibits glucocorticoid receptor activity. upregulation of these and other pro-inflammatory Mifepristone reduces the hyperglycemia associ- mediators may stimulate production of α-MSH ated with Cushing disease. Resolution of the bio- thereby leading to the pigmentation. chemical defect will result in normalization of HIV-induced cytokine dysregulation typically ACTH and α-MSH levels. Over time, the pigmen- parallels decreasing CD4+ T-cell counts (Feller tation may eventually resolve. et al. 2014a). 24 E.T. Stoopler and F. Alawi

More commonly, OMH may arise in response pigmentation may be difficult. The appearance, to treatment with a number of different medica- extent, and intensity of OMH is also similar to tions frequently used to treat HIV/AIDS and its that observed in other disorders known to induce associated complications; zidovudine (azidothy- mucocutaneous pigmentation. The diagnosis of midine [AZT]; nucleoside reverse transcriptase HIV-associated pigmentation is rendered if the inhibitor) is just one example (Feller et al. pigment initially appears or becomes exacerbated 2014a). The pigment frequently appears within after the diagnosis of HIV infection or following the first few weeks after initiation of the therapy. the initiation of therapy (Feller et al. 2014a). When the drug is withdrawn, the pigment usually diminishes. OMH is significantly more common Patient Management in HIV-seropositive patients treated with antire- Apart from possible esthetic concerns, there does troviral therapy (ART) than in ART-naïve not appear any clinical significance attributable to individuals. HIV-associated OMH. However, new onset oral Primary or secondary adrenocortical dysfunc- pigmentation in an individual deemed potentially tion may occur in as many as 20% of HIV patients high risk for HIV infection, including intravenous (Hruz 2014). This may be due to HIV-associated drug users, should prompt an evaluation for pos- viral or mycobacterial infections of the adrenal sible infection. gland or by medications used to treat the disease. Ritonavir (protease inhibitor) in combination with exogenous steroids is known to induce adrenal Peutz-Jeghers Syndrome insufficiency which, in turn, may induce the pig- mentation (Wood et al. 2015). Peutz-Jeghers syndrome (PJS) is an autosomal dominant disorder associated with oral and peri- Pathophysiology oral melanocytic pigmentation, benign The pathogenesis of HIV-associated pigmentation hamartomatous polyps of the gastrointestinal varies depending on the etiologic agent. Similar to tract, and increased risk for developing malignan- other forms of OMH, the pigmentation is usually cies of the gastrointestinal tract, breast, uterine the result of increased melanogenesis without a cervix, ovary, pancreas, and other anatomic sites change in melanocyte number. The pigment is (Riegert-Johnson et al. 2009). The risk is esti- concentrated within the basal layer of the stratified mated to be 18-fold higher than that of the general squamous epithelium and accompanied by mela- population. The hyperpigmentation often mani- nin incontinence within the papillary lamina pro- fests early in life and may be the first sign of pria (Feller et al. 2014a). The pigment is often disease in some patients. easily visualized in biopsy tissue with routine light microscopy. HIV-induced cytokine Epidemiology dysregulation and AZT and other medications Since PJS is a rare disorder, reliable estimates of may also induce pigmentation by stimulating incidence and prevalence are lacking. Nonethe- melanocytic hyperplasia accompanied by an less, PJS has an estimated incidence of 1 in increase in melanin synthesis. 8000–200,000 live births without gender or racial predilection (Riegert-Johnson et al. 2009). Mor- Clinical-Pathologic Features tality associated with PJS is usually cancer The pigmentation may manifest as multiple dis- related. crete light to dark brown macules or as patchy and diffuse. The coloration may appear anywhere Etiology within the oral cavity, but the gingiva tends to be Approximately 75% of all PJS patients harbor a the most commonly affected site. In darker- germline mutation in the SKT11 (LKB1) gene skinned individuals, differentiating located on chromosome 19p13.3 (Meserve and HIV-associated pigment from physiologic Nucci 2016). The remaining patients do not have Pigmented Lesions of the Oral Mucosa 25

freckling of the perioral skin (Ponti et al. 2016) (Fig. 32). The pigmented macules may coalesce to produce broader areas of pigmentation. Less com- monly, intraoral pigmentation may also be observed; the tongue and buccal and/or labial mucosae are typically affected. Pigmented spots are also commonly observed on the fingertips. The pigmentation typically presents during infancy, childhood, or adolescence, and is often the first sign of PJS. At least some of the pigmen- tation may spontaneously resolve with age. A biopsy of a pigmented lesion usually reveals Fig. 32 Perioral melanosis associated with Peutz-Jeghers nonspecific histopathology (Ponti et al. 2016). syndrome There is increased melanin pigmentation within the basal epithelial layer and melanin inconti- known STK11 mutations; the genetic cause of nence within the papillary lamina propria. There these patients’ disease remains undetermined. may also be evidence of melanocytic hyperplasia. Mutations in STK11-interacting proteins have Note that while highly characteristic, the pat- not yet been found in these latter patients. Thus, tern of labial and perioral pigmentation is not it has been suggested that these patients may have pathognomonic for PJS. Laugier-Hunziker pig- large STK11 gene rearrangements that cannot be mentation is an acquired and idiopathic form of identified by routine molecular testing (Meserve pigmentation that frequently mimics PJS and and Nucci 2016). should be considered in the differential diagnosis (Alawi 2013). However, Laugier-Hunziker pig- Pathophysiology mentation typically manifests during adulthood STK11 is serine-threonine kinase that directs and may be accompanied by pigmentation of the energy sensing and nutrient metabolism through nails. Patients with Laugier-Hunziker pigmenta- activation of an array of downstream factors tion do not exhibit STK11 mutations, and they do (Shorning and Clarke 2016). Together, STK11 not manifest with gastrointestinal polyps. and its phosphorylated substrates help to regulate Apart from the gastrointestinal polyps and can- cellular metabolism, proliferation, polarity, and cer, other systemic complications may include differentiation by maintaining and monitoring cel- intussusception, rectal bleeding, iron deficiency lular energy homeostasis. STK11 also contributes anemia, and development of ovarian cysts to genomic stability by participating in DNA (Riegert-Johnson et al. 2009). double-strand break repair. It is apparent that STK11 plays an important Patient Management role in melanocyte biology since the mucocutane- The development of labial and perioral pigmenta- ous pigmentation is observed in essentially all tion early in life should prompt genetic testing for patients with PJS (Ponti et al. 2016). Moreover, PJS (Meserve and Nucci 2016). In patients with a the hyperpigmentation can be observed in known family history or in newly diagnosed STK11-deficient murine models (Meserve and patients, surveillance strategies should be Nucci 2016). Nonetheless, the mechanisms by designed to ensure continuous and lifelong clini- which loss of STK11 function induces hyper- cal monitoring. Surgical treatment may be needed pigmentation remain unclear. to remove potentially obstructive gastrointestinal polyps. Iron supplementation may be necessary Clinical-Pathologic Features for a subset of patients who are anemic. Prognosis PJS is commonly associated with multiple mela- is primarily related to the occurrence of cancer notic macules of the lips accompanied by diffuse (Meserve and Nucci 2016). The pigmentation is 26 E.T. Stoopler and F. Alawi not symptomatic and does not require treatment While an amalgam may be blue gray to unless there is an esthetic concern. black in color, and thus the mucosa may appear clinically pigmented, the mucosa is not actually pigmented (Alawi 2013). The coloration is due Exogenous Causes of Clinical to the visualization of metallic particles embed- Pigmentation ded within the lamina propria and/or submu- cosa. Similarly, graphite tattoos may appear Tattoos: Amalgam, Graphite, clinically identical to amalgam tattoos and Ornamental (Fig. 37). Graphite tattoos are caused by the mucosal implantation of graphite particles typ- The most common nonphysiologic source of oral ically originating from the tip of a pencil (Alawi mucosal coloration is exogenous and not endoge- 2013). These tattoos are usually the result of nous in origin (Alawi 2013). Amalgam tattoos are accidental trauma. the most common cause of oral “pigmentation” Ornamental or intentional oral mucosal tattoos (Alawi 2013). They result from the iatrogenic have long been a custom in some parts of the mucosal implantation of amalgam particles usu- world, including within specific African tribal ally during the course of a dental procedure. communities, which has been described previ- Amalgam tattoos are macular, usually small and ously in this chapter (Gondak et al. 2012). The frequently identified in close proximity to tattoo ink is usually plant based and may be com- amalgam-restored teeth or in areas where such bined with other carbon-based substances such as teeth were previously present (Figs. 33a–c, 34, burnt wood, plastic, India ink, or even pen ink. 35, and 36). Amalgam tattoos may be identified Ornamental tattooing is a growing trend in other in any oral location, but the gingiva and alveolar parts of the world, including Eastern European mucosa are most commonly affected. and Western countries (Fig. 38).

Fig. 33 Amalgam tattoo appearing clinically as a black (c) views confirming presence of amalgam particles (Photo pigmented lesion on the labial gingiva of the tooth 16 (a). courtesy: Professor Camile Farah, Perth Oral Medicine & Same lesion noted on multislice CT sagittal (b) and axial Dental Sleep Centre, Perth, WA, Australia) Pigmented Lesions of the Oral Mucosa 27

Fig. 36 Amalgam tattoo appearing clinically as black pigmented lesion in a 65-year-old female presenting on the buccal mucosa adjacent to a heavily restored molar (Photo courtesy: Professor Camile Farah, Perth Oral Med- Fig. 34 Amalgam tattoo appearing clinically as black icine & Dental Sleep Centre, Perth, WA, Australia) pigmented lesion on the attached mucosa adjacent to heavily restored molar (Photo courtesy: Professor Camile Farah, Perth Oral Medicine & Dental Sleep Centre, Perth, WA, Australia)

Fig. 35 Biopsy-proven amalgam tattoo appearing clini- cally as black pigmented lesion in a 30-year-old female at the mucogingival junction adjacent to virgin canine and premolar teeth with braces. Lesion was remnant from Fig. 37 Biopsy-proven graphite tattoo in a 63-year-old heavily restored primary dentition (Photo courtesy: Profes- female appearing clinically as a gray pigmented lesion on sor Camile Farah, Perth Oral Medicine & Dental Sleep the gingiva (Photo courtesy: Professor Camile Farah, Perth Centre, Perth, WA, Australia) Oral Medicine & Dental Sleep Centre, Perth, WA Australia) 28 E.T. Stoopler and F. Alawi

2016). Examples include lead, mercury, silver, and bismuth, among others. Exposure to these metals most commonly occurs through continual ingestion of contaminated drinking water or foods, such as fish and seafood, or through occu- pational exposure. In most cases, the discoloration appears as a black-blue line that follows the out- lines of the marginal gingiva (Alawi 2013; Hassona et al. 2016). This is known as a Burton or Burtonian line in individuals with chronic (Pearce 2007). Similar to an amalgam tattoo, a Burton line is not true pigmentation. Fig. 38 Ornamental ink tattooing involving the mandib- Instead, a chemical reaction occurs between sulfur ular labial mucosa in a female patient which reads “In My ions released by the regional oral flora and the ” Stars (Photo courtesy: Clinical Associate Professor circulating lead. This results in the deposition of Ramesh Balasubramaniam, Oral Health Centre of Western fi Australia, School of Dentistry, University of Western lead sul de within the marginal gingiva leading to Australia, Perth, WA, Australia) the discoloration. “Mercury lines” and “bismuth lines” develop via similar types of chemical reac- For focal areas of discoloration, a biopsy tions with compounds released by oral bacteria. diagnosis is first warranted since mucosal tat- Mucocutaneous is due to the accumulation toos may be difficult to reliably differentiate of silver metal or silver sulfide within the lamina from benign and malignant melanocytic and/or propria and submucosa and often manifests as vascular pathologies (Alawi 2013). In instances generally diffuse bluish mucosal discoloration where metallic amalgam particles may be evi- (Kim et al. 2009). dent on a radiograph, this may preclude the need Identifying and eliminating the source of the for biopsy diagnosis. After histopathologic toxicity is critical to ensure there are no long- diagnosis, no additional intervention is needed. lasting systemic and neurologic effects. Chela- While the esthetic concerns associated with tion therapy under professional supervision may amalgam, graphite, and ornamental tattooing be beneficial, but the extent of exposure and the may be significant for some individuals, treat- specific type of metal toxicity dictates which ment is not indicated. However, if treatment is chelating agent(s) will be used and the mode of requested, low-energy lasers can be used to administration (Caito and Aschner 2015). remove the tattoos (Yilmaz et al. 2010). Sub- Succimer (2,3-dimercaptosuccinic acid epithelial connective tissue grafts followed by [DMSA]) is an orally administered chelating laser de-epithelialization or gingivoplasty have agent typically used for lead, mercury, or arsenic also been used with success (Campbell and Deas poisoning. Intravenous dimercaprol can be used 2009; Thumbigere-Math and Johnson 2014). in severe cases. Calcium-disodium ethylenedia- Alternatively, simple cold steel surgical exci- minetetraacetic acid (EDTA) is also sion of affected tissues is a straightforward recommended for lead poisoning. A mono- approach. isoamyl ester derivative of DMSA may be more effective at chelating mercury than succimer. It should be noted that while succimer has a limited Metal-induced Discoloration side-effect profile, intravenously administered chelating agents can be associated with a wide Chronic exposure to various metals is known to array of serious adverse effects, including renal induce discoloration but not “true” pigmentation failure, seizures, coma, and even death (Caito of the oral mucosa (Alawi 2013; Hassona et al. and Aschner 2015). Pigmented Lesions of the Oral Mucosa 29

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