Pigmented Lesions of the Oral Mucosa

Transcription

1 Pigmented Lesions of the Oral Mucosa Eric T. Stoopler and Faizan Alawi Abstract Pigmented lesions of the oral mucosa are encountered on a routine basis in clinical practice. Oral health-care providers must assess several parameters associated with pigmented lesions, such as location, shape, color, and size. Etiology of pigmented lesions may be attributed to a local phenomenon and/or associated with an underlying systemic disorder. Diagnostic and therapeutic modalities must be carefully considered as these lesions encompass the spectrum of clinical pathology, ranging from benign to malignant. Clinicians should conduct a thorough medical history and relevant physical examination for patients with pigmented lesions to identify possible adrenal, gastrointestinal, or genetic disorders that are commonly associated with these types of lesions. If a systemic disorder is suspected, the patient should be promptly referred to the appropriate health-care provider for further evaluation and management. Multidisciplinary care is often necessary to effectively manage patients with these conditions. This chapter provides a E.T. Stoopler (*) Department of Oral Medicine, University of Pennsylvania School of Dental Medicine, Philadelphia, PA, USA ets@upenn.edu F. Alawi Department of Pathology, University of Pennsylvania School of Dental Medicine, Philadelphia, PA, USA falawi@upenn.edu # Springer International Publishing AG 2017 C.S. Farah et al. (eds.), Contemporary Oral Medicine, DOI / _17-1 contemporary perspective of pigmented lesions of the oral mucosa and is intended to serve as a practical clinical resource for oral health-care providers. Keywords Oral mucosa Pigmentation Melanin Focal Multifocal Diffuse Systemic Genetic Exogenous Contents Introduction... 2 Focal Pigmentation... 2 Freckle/Ephelis... 2 Oral/Labial Melanotic Macule... 3 Oral Melanoacanthoma Melanocytic Nevus... 6 Malignant Melanoma... 8 Multifocal/Diffuse Pigmentation Physiologic Pigmentation Drug-Induced Melanosis Smoker s Melanosis Post-inflammatory (Inflammatory) Hyperpigmentation Laugier-Hunziker Pigmentation Pigmentation Associated with Systemic or Genetic Disorders Adrenal Insufficiency (Addison Disease) Cushing Disease Human Immunodeficiency Virus (HIV): Associated Pigmentation Peutz-Jeghers Syndrome Exogenous Causes of Clinical Pigmentation Tattoos: Amalgam, Graphite, and Ornamental Metal-induced Discoloration

2 2 E.T. Stoopler and F. Alawi Conclusion and Future Directions Cross-References References Introduction The mucous membranes lining the oral cavity are not uniformly colored and dependent upon the specific anatomic location; healthy tissue commonly ranges in color from white to red-purple. This is due to the interaction of various tissues that compose the mucosal lining, including presence or absence of keratin on the surface epithelium, location and presence of vascular structures in the stroma, existence of adipocytes, and the lack of melanin pigmentation in the basal cell layer of the epithelium. Pigment deposition, whether physiologic or pathologic, or attributed to endogenous or exogenous substances, will impart gray, blue, brown and/or black color changes to the oral mucosa. The most common endogenous sources of pigmentation are melanin, hemoglobin, and hemosiderin, while exogenous sources of pigmentation are usually attributed to traumatic or iatrogenic events that result in deposition of foreign material directly into the mucosal tissues. Several parameters associated with pigmented lesions, such as location, shape, color, and size, must be assessed in order for clinicians to appropriately evaluate and manage the condition, as pathology of pigmented lesions ranges from benign to malignant. Clinicians should conduct a thorough medical, family, and social history, as well as a relevant physical examination for patients with pigmented lesions, to identify possible adrenal, gastrointestinal, or genetic disorders that are commonly associated with these types of lesions. If a systemic disorder is suspected, the patient should be promptly referred to the appropriate health-care provider for further evaluation and management. Multidisciplinary care is often necessary to effectively manage patients with these conditions. This chapter provides a contemporary perspective of pigmented lesions of the oral mucosa focusing on those associated with melanin and will discuss focal pigmentation conditions, multifocal or diffuse pigmentation conditions, pigmentation associated with systemic or genetic disorders, and exogenous causes of clinical pigmentation (Table 1). Melanocytes are derived from neural crest cells and are located in the basal epithelial layer of squamous mucous membranes (Meleti et al. 2008). The functions of melanocytes are not fully understood, but the melanin produced by these cells absorb ultraviolet light, scavenge reactive oxygen species, and determine skin, hair, and eye color (Meleti et al. 2008; Feller et al. 2014a, b). Oral melanocytes are regularly interspersed between basal keratinocytes, and melanin from the melanocytes are transported and transmitted to epithelial cells via dendritic migration of melanosomes (melanin-containing vesicles). The ratio of melanocytes to keratinocytes in the basal epithelial layer ranges from 1:10 to 1:15 (Feller et al. 2014a, b). Two chemically distinct types of melanin exist, eumelanin (brown-black) and pheomelanin (red/yellow), and melanogenesis is considered a mixed process between these melanin types, with proportions of eumelanin and pheomelanin being genetically determined (Feller et al. 2014a, b). There are no numerical or structural differences in oral melanocytes between Table 1 Pigmented lesions of the oral mucosa I. Focal pigmentation conditions a. Freckle/ephelis b. Oral/labial melanotic macule c. Oral melanoacanthoma d. Melanocytic nevus e. Malignant melanoma II. Multifocal/diffuse pigmentation conditions a. Physiologic pigmentation b. Drug-induced melanosis c. Smoker s melanosis d. Post-inflammatory (inflammatory) hyperpigmentation e. Laugier-Hunziker pigmentation III. Pigmentation associated with systemic or genetic disorders a. Adrenal insufficiency (Addison disease) b. Cushing disease c. Human immunodeficiency virus (HIV) associated pigmentation d. Peutz-Jeghers syndrome IV. Exogenous causes of clinical pigmentation a. Tattoos amalgam, graphite and ornamental b. Metal induced discoloration

3 Pigmented Lesions of the Oral Mucosa 3 light-skinned and dark-skinned individuals except that in the latter, the melanosomes are larger and more numerous (Feller et al. 2014a, b). Several factors likely determine intraoral mucosal color, including number and melanogenic activity of melanocytes, differences in number, size and distribution of melanosomes, difference in the type of melanin, and the masking effect of heavily keratinized epithelium (Feller et al. 2014a, b). Focal Pigmentation Freckle/Ephelis Epidemiology A freckle (ephelis) is a hyperpigmented macule commonly observed on the facial and perioral skin. They usually develop during the first decade of life and are more common in light-skinned individuals with blonde or red hair (Gaeta et al. 2002; Hatch 2005). There is no gender predilection, and the color intensity and frequency of freckles typically decrease after adolescence (Gaeta et al. 2002; Hatch 2005). Etiology Freckles are thought to be developmental in origin (Gaeta et al. 2002; Hatch 2005). Genetic polymorphisms associated with the melanocortin-1 receptor (MC1R) gene and chromosome 4q32- q34 have been strongly associated with freckle development (Bastiaens et al. 2001). Pathophysiology Freckles are due to an increase in melanin production without an increase in the number of melanocytes and become more pronounced after sun exposure. They are also associated closely with a history of symptomatic childhood sunburns (Bliss et al. 1995). Clinical-Pathologic Features Freckles appear as a uniformly tan- or browncolored, oval or round macule, between 1 and 3 mm in size on sun-exposed cutaneous surfaces (Gaeta et al. 2002; Hatch 2005) (Fig. 1). They have regularly defined borders, are not elevated above the skin surface, and are asymptomatic (Gaeta et al. 2002; Hatch 2005). They often appear on the perioral skin and vermillion border of the lips with increased frequency on the lower lip (Hatch 2005). Although many individuals have less than ten lesions, due to the great variability in the number of lesions present, some may have hundreds of freckles (Gaeta et al. 2002; Hatch 2005). Histopathologically, freckles exhibit abundant melanin deposition in the basal cell layer of the epidermis without elongation of rete ridges (Hatch 2005). Patient Management Treatment is typically not indicated for freckles in childhood or adolescence (Hatch 2005). Sunscreens may help prevent darkening of existing lesions and prevent the appearance of new lesions (Bliss et al. 1995). Freckles of cosmetic concern may be treated with chemical peels, laser therapy, and/or cryotherapy. MC1R gene variants have been associated with an increased risk for sporadic cutaneous melanoma (Pasquali et al. 2015). Oral/Labial Melanotic Macule Epidemiology A melanotic macule is a benign pigmented lesion that may occur on intraoral mucosal surfaces (oral melanotic macule) or on the lips (labial melanotic macule) (Tarakji et al. 2014). They are considered to be the most common oral mucosal lesions of melanocytic origin and are also termed focal melanosis (Alawi 2013; Muller 2010). Oral/labial melanotic macules are present in up to 3% of the population, are typically observed in patients in the fourth and fifth decades, and have a 2:1 female predilection (Hatch 2005; Meleti et al. 2008; Muller 2010). Etiology The etiology of oral/labial melanotic macules has not been definitively determined but may represent a reactive or a physiologic process (Meleti et al. 2008).

4 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 interdental gingiva between 41 and 42 (Photo courtesy: Professor 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 within the basal cell layer, the lamina propria, or both (Meleti et al. 2008). The etiology of these lesions is unclear; however, sun exposure does not appear to be a precipitating factor. Clinical-Pathologic Features Oral/labial melanotic macules are solitary, wellcircumscribed lesions that are typically less than 1 cm in diameter (Alawi 2013; Kauzman et al. 2004). They are uniformly tan to dark brown, round or oval, and asymptomatic (Kaugars et al. Fig. 4 Biopsy-proven melanotic macule appearing as a faint brown lesion on the right soft palate (Photo courtesy: Professor Camile Farah, Perth Oral Medicine & Dental Sleep Centre, Perth, WA, Australia) 1993; Shen et al. 2011). Overall, labial melanotic macules are the most common type of macules observed with the lower lip vermillion border predominantly affected (Kaugars et al. 1993; Shen et al. 2011). In contrast to freckles, labial melanotic macules do not darken after exposure to the sun (Lim et al. 2014; Meleti et al. 2008). Oral melanotic macules may appear on any surface but

5 Pigmented Lesions of the Oral Mucosa 5 Fig. 5 Biopsy-proven melanotic macule involving the hard palate demonstrating irregular pigmentation and border viewed with white light (a) and with optical fluorescence imaging VELscope Vx (b) showing loss of fluorescence limited to lesion with no diascopy (Photo courtesy: Professor Camile Farah, Perth Oral Medicine & Dental Sleep Centre, Perth, WA, Australia) 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 typically demonstrate elongated rete ridges (Alawi 2013). Fig. 6 Melanotic macule. Melanin pigmentation is noted in the basal epithelial layer (hematoxylin and eosin, 200) are most commonly observed on the buccal mucosa, gingiva, and palate (Kauzman et al. 2004) (Figs. 2, 3, 4, and 5a, b). Intraoral lesions are often larger than those located on the lips (Meleti et al. 2008). Histopathological analysis of melanotic macules reveals an increase in melanin in the basal and parabasal layers of normal stratified squamous epithelium without an 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 alveolar 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 of these lesions may be accomplished by scalpel, cryosurgery, electrocautery, or laser ablation (Alawi 2013; Lim et al. 2014). Oral Melanoacanthoma Epidemiology Oral melanoacanthoma represents a benign melanocytic lesion that is most commonly

6 6 E.T. Stoopler and F. Alawi Fig. 7 Oral melanoacanthoma affecting the buccal mucosa Fig. 8 Dendritic melanocyte (arrow) within the stratum spinosum observed in dark-complexioned females between 30 and 50 years of age (Arava-Parastatidis et al. 2011). This condition has been reported in Hispanic, Asian, and Caucasian patients and has an overall female predilection (Arava-Parastatidis et al. 2011). Etiology Oral melanoacanthoma is of unknown etiology (Gondak et al. 2012; Muller 2010). Pathophysiology The pathophysiologic mechanism for oral melanoacanthoma is most consistently associated with acute regional trauma or chronic irritation (Alawi 2013; Arava-Parastatidis et al. 2011). Clinical-Pathologic Features Oral melanoacanthoma typically presents as a diffuse, rapidly enlarging area of macular pigmentation 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 on the buccal mucosa followed by the palate, lips, gingiva, and tongue and may present unilaterally or bilaterally (Alawi 2013; Arava- Parastatidis et al. 2011). This condition is primarily asymptomatic; however, some patients report burning sensations and/or pruritus associated with these lesions (Cantudo-Sanagustín et al. 2016). Histologically, oral melanoacanthoma is characterized by spongiotic epithelium containing dendritic pigmented melanocytes throughout the lesional epithelium (Alawi 2013) (Fig. 8). A mild to moderate inflammatory infiltrate composed of lymphocytes and occasional eosinophils is observed in the underlying connective tissue (Alawi 2013). Patient Management Treatment of oral melanoacanthoma is typically not indicated after diagnosis has been established. An incisional biopsy is necessary to rule out malignant melanoma as it is considered in the differential diagnosis of these lesions due to its ominous clinical presentation (Alawi 2013). Spontaneous regression of oral melanoacanthoma has been observed after biopsy, and recurrence of these lesions is rare (Alawi 2013; Arava- Parastatidis et al. 2011). Malignant transformation of oral melanoacanthoma has not been reported (Kauzman et al. 2004). Melanocytic Nevus Epidemiology Melanocytic nevi, commonly referred to as moles, represent a group of benign tumors that

7 Pigmented Lesions of the Oral Mucosa 7 develop due to melanocytic growth and proliferation (Alawi 2013; Hatch 2005). Cutaneous nevi are common and typically develop during childhood with most cutaneous lesions present before the age of 35 (Marangon Junior et al. 2015). In addition, Caucasians tend to develop cutaneous nevi more frequently than blacks or Asians (Marangon Junior et al. 2015). The intramucosal nevus is the most frequently observed type of oral nevus followed by the blue nevus, compound nevus, junctional nevus, and combined nevus, in decreasing order of frequency (Alawi 2013). Oral melanocytic nevi are frequently observed in the third to fourth decades of life, and while the total number of nevi tends to be higher in males, oral melanocytic nevi are more common in females (Alawi 2013). Etiology In general, melanocytic nevi are acquired lesions with both environmental and genetic factors thought to play a role in the development of cutaneous lesions (Alawi 2013; Muller 2010). Sun exposure is a well-recognized environmental factor for development of cutaneous nevi (Lim et al. 2014). Recent studies have demonstrated cutaneous nevi exhibiting somatic, activating mutations in the BRAF, HRAS, and NRAS protooncogenes (Alawi 2013; Meleti et al. 2008). It remains unclear if similar mutations are implicated as the etiology of oral melanocytic nevi (Alawi 2013). 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 differentiating clinical and histologic features (Alawi 2013). Melanocytic proliferation can be considered in three phases that correspond to each of the aforementioned nevi types: (1) proliferation of benign neoplastic melanocytes along the epithelial-mesenchymal junction (i.e., junctional nevus), (2) migration of these cells into the mesenchymal compartment (i.e., compound nevus), and (3) loss of the junctional component of the nevus so all remaining cells are located within the subepithelial compartment (intramucosal nevi) (Meleti et al. 2008). Blue nevi are melanocytic lesions that typically appear slate blue to blue black and account for up to 35% of all oral nevi (Pinto et al. 2003). They are categorized into the common type and the less frequently encountered cellular type, and while each has specific characteristic histopathologic features, both types harbor melanin particles deep to the surface so that reflected light appears blue to the observer (Pinto et al. 2003). Darkly pigmented blue nevi may be clinically indistinguishable from other types of melanocytic nevi. Clinical-Pathologic Features Cutaneous junctional nevi commonly appear as a sharply demarcated macule less than 6 mm in diameter with brown or blue coloration (Alawi 2013). Compound nevi may be macular or slightly elevated, soft with a relatively smooth surface, while intradermal (cutaneous counterpart to intramucosal) nevi exhibits loss of pigmentation and a papillomatous surface with possible central hair growth (Alawi 2013). Oral melanocytic nevi have no distinguishing clinical characteristics; however, they are usually asymptomatic, solitary, well circumscribed, less than 1 cm, macular or nodular in appearance, and brown or blue in color (Alawi 2013) (Figs. 9 and 10). It is Fig. 9 Intramucosal nevus (arrow) located on the palate (Courtesy of Dr. Edward Marcus)

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

9 Pigmented Lesions of the Oral Mucosa 9 Fig. 13 Blue nevus. Spindle-shaped melanocytes (arrows) are embedded within a densely fibrotic lamina propria (hematoxylin and eosin, 200) development of melanoma, with greater than 50 nevi increasing the risk of melanoma approximately four- to fivefold (Lim et al. 2014). Overall, the risk of malignant transformation of cutaneous nevi to melanoma is low, and current evidence does not suggest that oral melanocytic nevi are markers for development of oral malignant melanoma (Meleti et al. 2008). Malignant Melanoma Epidemiology Malignant melanoma is a neoplasm of melanocytic origin with most cases occurring on the skin. While the incidence of malignant melanoma is lower compared to nonmelanoma skin cancers, it accounts for the vast majority of skin cancer deaths (Lee et al. 2017). Malignant melanoma is most common among white populations residing in Sunbelt regions of the world (Berwick et al. 2016). International incidence of melanoma 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 persons 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 cancerrelated deaths in the United States (Gandhi and Kampp 2015). Incidence of malignant melanoma in European countries varies widely with approximately 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 melanoma 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). Overall, there is a male predilection for the condition, but incidence is increasing in younger women of child-bearing age (Lim et al. 2014). Prognosis of malignant melanoma is dependent on depth of invasion, lesion thickness, and stage of disease at diagnosis utilizing the Clark system, the Breslow classification, and the tumor node metastasis (TNM) staging criteria, respectively (Lim et al. 2014). Thicker lesions and advanced-stage disease have a much lower 5-year survival rate, and metastatic melanoma is associated with a median survival time of 6 to 9 months (Lim et al. 2014). Oral malignant melanoma occurs much less frequently than its cutaneous counterpart; it comprises less than 1% of all malignant melanomas in the United States and 0.26% of all oral cavity cancers worldwide (Hashemi Pour 2008). Data suggests oral malignant melanoma may occur more frequently in certain countries, such as Japan and Uganda, and dark-skinned races have a greater relative incidence of oral malignant melanoma and higher mortality rate associated with this condition (Tarakji et al. 2014). Generally, oral malignant melanoma occurs at a slightly higher frequency in males and generally presents after 50 years of age with the peak age of diagnosis between 65 and 79 years (Alawi 2013; Femiano

10 10 E.T. Stoopler and F. Alawi et al. 2008). Unlike cutaneous malignant melanoma, histopathologic parameters cannot be reliably used to determine prognosis of oral malignant melanoma (Alawi 2013). Oral malignant melanoma is associated with a very poor prognosis; 5-year survival rates range between 5% and 50% with a large cluster at 10 25% (Femiano et al. 2008). Less than 10% of patients with distant metastases survive greater than 5 years, and the 10-year survival rate has been reported to be 0% (Hashemi Pour 2008). Etiology While the cause of malignant melanoma has not been clearly defined, multiple risk factors have been associated with onset of the cancer (Lim et al. 2014). Exposure to the sun is the most important environmental cause of cutaneous malignant melanoma, with ultraviolet radiation, primarily ultraviolet A type, being most associated with tumorigenesis and development of the disease (Lim et al. 2014). In light-skinned populations, the main nonsolar source of exposure to ultraviolet light are tanning beds, and several recent studies demonstrate that the risk of malignant melanoma is increased by 20% for those who ever used indoor tanning (Lim et al. 2014). There is a relationship between a prior personal or family history and malignant melanoma risk with approximately 10% of malignant melanomas occurring in familial clusters (Lim et al. 2014). Mutations have been identified in two highpenetrance susceptibility genes, the cyclindependent kinase inhibitor 2A (CDKN2A) on chromosome 19p21 and cyclin-dependent kinase 4 (CDK4) on chromosome 12q14 (Lim et al. 2014). The MC1R gene has been identified as a low penetrance malignant melanoma susceptibility gene, and alterations of the BRAF, HRAS, and NRAS proto-oncogenes, and alteration or loss of PTEN function, have been associated with malignant melanoma development (Lim et al. 2014). As discussed previously, the number of melanocytic nevi represents an independent risk factor for development of malignant melanoma, with greater than 50 nevi increasing the risk of malignant melanoma approximately four- to fivefold (Lim et al. 2014). Sun protection at an early age may lower the subsequent risk of malignant melanoma (Lim et al. 2014; MacLennan et al. 2003). The etiology of oral malignant melanoma is unknown, and unlike its cutaneous counterpart, risk factors for development have not been clearly defined (Femiano et al. 2008). Pathophysiology Malignant melanomas may either develop de novo or from a preexisting benign melanocytic lesion (Chatzistefanou et al. 2016). Melanocytes are neuroectodermal derivatives and normally migrate to the skin and other ectodermally derived mucosae (Femiano et al. 2008). Less frequently, melanocytes migrate to endodermally derived mucosae, such as those found in the head and neck, and melanocytes have been observed in the deep stroma of oral mucosa (Femiano et al. 2008). Due to both extrinsic and intrinsic factors previously described, proliferation of malignant melanocytes gives rise to a variety of melanoma types. Clinical-Pathologic Features Malignant melanoma can have a variety of clinical appearances, with early lesions typically characterized by a macule or plaque with different hues (brown, black, blue, red, or white) or occasionally as an ulceration that does not heal (Lim et al. 2014). The ABCDE acronym (asymmetry, border irregularity, color variegation, diameter greater than 6 mm, and evolution or surface elevation) is commonly used to initially evaluate pigmented cutaneous lesions, although not all malignant melanomas present with all of these features (Lim et al. 2014). The anatomic distribution of malignant melanoma differs by sex and age. In men, lesions are commonly located on the trunk (55%), especially the back (39%), while in women, 42% of malignant melanoma lesions are localized to the lower extremities, with 24% on the lower leg (Lim et al. 2014). Four major clinical-pathologic subtypes of non-oral malignant melanoma have been described: superficial spreading melanoma, lentigo maligna melanoma, acral lentiginous

11 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, Darlinghurst, NSW, Australia) Fig. 16 Nodular melanoma on the toe (5.7 mm in depth) in a 67-year-old male (Photo courtesy: Dr. Simon Lee, Head of Surgery, The Skin Hospital, Darlinghurst, NSW, Australia) Fig. 15 Superficial spreading melanoma of the cheek (0.7 mm in depth) in a 71-year-old male (Photo courtesy: Dr. Simon Lee, Head of Surgery, The Skin Hospital, Darlinghurst, NSW, Australia) melanoma, and nodular melanoma (Lim et al. 2014). Superficial spreading melanoma is the most common subtype, accounting for 70% of all melanoma diagnoses (Lim et al. 2014). Most lesions of this type occur de novo, and, clinically, a superficial spreading melanoma appears variegated 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 producing melanin, resulting in a nonpigmented amelanotic macule. Lentigo maligna 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 presents as a slowly enlarging, asymmetric macule with irregular borders that is variably pigmented with tan, brown, black, and possibly white colors (Lim et al. 2014). Acral lentiginous melanoma, the least common subtype, accounts for less than 5% of all melanomas but accounts for 70% of melanomas seen in African-Americans (Lim et al. 2014). Clinically, it affects hairless areas like subungual, palmar, and plantar regions and

12 12 E.T. Stoopler and F. Alawi Fig. 17 Malignant melanoma present on the lower labial mucosa mucous membranes and presents as a variably colored macule, usually brown or black, which develops irregular borders and increases in size over time (Lim et al. 2014). Oral malignant melanoma, however, has no such distinctive clinical appearance and is often initially asymptomatic. The lesion typically begins as a brown to black macule with irregular borders and may even lack pigment (Hashemi Pour 2008) (Fig.17). Lesions are relatively soft to palpation and may be accompanied by erythema and/or ulceration, which can potentially cause pain (Mohan et al. 2013). Tooth mobility or spontaneous exfoliation, root resorption, anesthesia/paresthesia, and bone loss may be evident (Mohan et al. 2013). Diffuse, contiguous mucosal pigmentation should be viewed suspiciously as possible malignant melanoma compared to diffuse, noncontiguous pigmentation (Alawi 2013). While any mucosal site may be affected, the palate is the most common intraoral location of oral malignant melanoma followed by the maxillary gingiva/alveolar crest (Femiano et al. 2008) (Fig.18a, b). There may be radiographic evidence of moth-eaten or irregular bone destruction associated with these lesions, and cervical lymph nodes may be palpable due to metastasis at initial presentation (Hashemi Pour 2008). Microscopically, superficial spreading melanoma, lentigo maligna melanoma, and acral lentiginous melanoma demonstrate a lateral and superficial spread of melanocytic tumor cells 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 characterized by vertical growth of malignant melanocytes into the connective tissue, which typically occurs early in the disease process. The tumor usually appears as pleomorphic, spindle-shaped, or epithelioid cells arranged in loosely aggregated sheets and cords. Oral malignant melanomas are usually characterized by sheets or islands of malignant melanocytes within the connective tissue with possible pagetoid spread (Alawi 2013; Chatzistefanou et al. 2016) (Fig. 19). Poorly differentiated tumors may exhibit only minimal pigment or none at all (Fig. 20). Like its cutaneous counterpart, oral malignant melanomas exhibit an initial radial growth phase, typically followed by a vertical pattern of growth with deeper tissue invasion (Chatzistefanou et al. 2016). The presence of malignant cells in the lamina propria and a high tumor mitotic rate are characteristic of invading activity (Chatzistefanou et al. 2016). Immunohistochemistry studies using antibodies directed against HMB45, S100, MART1, and/or microphthalmia-associated transcription factor (MitF) are necessary for definitive diagnosis of oral malignant melanoma (Muller 2010) (Fig. 21). Patient Management Biopsy is mandatory for any persistent solitary pigmented lesion, as they can be representative of a variety of processes, from innocuous lesions to life-threatening malignant melanoma (Mohan et al. 2013). Once malignant melanoma is diagnosed, it is important, yet challenging, to determine if the lesion represents a primary malignancy or a metastasis from a distant site, as this information will dictate tumor staging and direct therapy (Alawi 2013). Surgical excision is the primary treatment modality for malignant melanoma, which is curative for most patients with early-

13 Pigmented Lesions of the Oral Mucosa 13 Fig. 18 Biopsy-proven gingival malignant melanoma in 67-year-old male appearing as multiple black pigmented lesions along the attached gingiva adjacent to upper anterior teeth (a). Hematoxylin- and eosin-stained histological section of lesion demonstrating brown pigment in malignant cells and superficial underlying connective tissue (b) (Photo courtesy: Professor Camile Farah, Oral Health Centre of Western Australia, School of Dentistry, University of Western Australia, Perth, WA, Australia) stage lesions (Chatzistefanou et al. 2016). Wide excision is recommended, but the recommended surgical margin varies, depending on the depth of the tumor (Lim et al. 2014). Lymph node dissection is typically performed on patients with clinically evident regional metastasis in the absence of distant metastasis (Chatzistefanou et al. 2016). Adjuvant systemic therapies have limited success in the treatment of advanced-stage malignant melanoma, which include interferon-a, high-dose interleukin 2, ipilimumab (a monoclonal antibody that works to activate the immune system by targeting CTLA-4, a protein receptor that downregulates the immune system), and bevacizumab (a recombinant humanized monoclonal antibody that blocks angiogenesis by inhibiting vascular endothelial growth factor-a) (Lim et al. 2014). The role of radiotherapy is limited since malignant melanoma is radio resistant compared with other cancers (Lim et al. 2014). Multifocal/Diffuse Pigmentation Physiologic Pigmentation Epidemiology Physiologic ( racial ) pigmentation is the most common multifocal or diffuse oral mucosal pigmentation; however, it is not directly related to skin color (Gaeta et al. 2002; Tarakji et al. 2014). It is typically observed in dark-skinned individuals, most commonly in African, Asian, or Mediterranean populations without gender predilection (Kauzman et al. 2004; Meleti et al. 2008). It is seen during the first two decades of life but may not be observed and/or of individual concern until later in life (Kauzman et al. 2004; Tarakji et al. 2014). Etiology The etiology of physiologic pigmentation has not been identified (Muller 2010).

14 14 E.T. Stoopler and F. Alawi Fig. 21 Anti-HMB45 immunohistochemical analysis. The malignant tumor cells (see Fig. 6) were strongly reactive with the melanocytic marker HMB45 intensity of the lesions may be influenced by hormones, smoking, and systemic medications (Muller 2010). Fig. 19 Mucosal melanoma. Sheets and cords of malignant melanocytes scattered throughout the lamina propria (hematoxylin and eosin, 100) Fig. 20 Amelanotic melanoma exhibiting only focal pigmentation (arrow). The tumor cells are poorly differentiated (hematoxylin and eosin, 200) Pathophysiology The increased pigmentation associated with this condition is attributed to increased melanocytic activity rather than an increase in numbers of melanocytes. It has been reported that color Clinical-Pathologic Features Physiologic pigmentation typically affects the gingiva, where it presents as a bilateral, welldemarcated, 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 associated 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 condition is characterized by the presence of increased amounts of melanin deposition within the basal cell layer (Gondak et al. 2012) (Fig. 24). Patient Management Diagnosis of physiologic pigmentation is typically made based on clinical appearance, and treatment is not indicated for this condition (Meleti et al. 2008). Biopsy may be indicated if pigmentation is of recent onset in adulthood and/or the patient reports physical symptoms that may be related to a systemic disorder, such as Addison disease, that may cause development of

15 Pigmented Lesions of the Oral Mucosa 15 Fig. 22 Physiologic pigmentation of the maxillary and mandibular gingiva Fig. 23 Physiological pigmentation in a patient of African heritage appearing as widespread brown and black pigmentation along the attached gingiva (Photo courtesy: Professor Camile Farah, Perth Oral Medicine & Dental Sleep Centre, Perth, WA, Australia) oral pigmentation (Muller 2010). This condition may be of esthetic concern to patients, and although procedures such as gingivectomy, laser therapy, and cryotherapy have been used to remove affected tissues, these lesions may eventually recur. The practice of gingival tattooing in females is a custom that is practiced among several African ethnic groups and may appear clinically similar to physiologic pigmentation (Rawal et al. 2007). Traditionally, products such as lantern soot and botanical resins are applied to the maxillary labial gingiva of preteen and teenaged females via needles and thorns to the affected surfaces (Brooks and Reynolds 2007, Rawal et al ) This practice is primarily for cosmetic reasons to make the teeth appear whiter, which is a highly desirable beauty mark in some African societies (Rawal et al. 2007) (Fig. 25). Fig. 24 Physiologic pigmentation. Anti-MART1 antibody was used to highlight normal melanocytes (arrows) residing in the basal epithelial layer Drug-Induced Melanosis Epidemiology Mucosal coloration can be induced by an array of medications. It has been estimated that 10 20% of all cases of acquired melanocytic pigmentation may be induced by drugs (Dereure 2001). Etiology Several medications have been implicated in drug-induced melanosis such as hormones and oral contraceptives; antipsychotics including chlorpromazine; antimalarial drugs such as hydroxychloroquine and quinacrine; chemotherapeutic agents including bleomycin, busulfan, fluorouracil, and imatinib; anti-retroviral agents including zidovudine; anti-fungal drugs such as ketoconazole; and anti-microbial agents including minocycline and tetracycline (Moraes et al. 2011; Alawi 2013; Yuan and Woo 2015).

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

17 Pigmented Lesions of the Oral Mucosa 17 Etiology Polycyclic amines, such as nicotine and benzopyrene, are chemical compounds in tobacco smoke that have demonstrated the ability to stimulate 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 production 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. 2004; Muller 2010). Clinical-Pathologic Features Smoker s melanosis typically presents as diffuse, patchy melanosis affecting the anterior vestibular maxillary and mandibular gingivae, buccal mucosa, labial commissures, lateral tongue, palate, and/or floor of the mouth (Muller 2010) (Fig. 27). The color of the lesions is typically brown to black (Alawi 2013). The areas of pigmentation dramatically increase during the first year of smoking and often correlate to the number of cigarettes smoked per day (Kauzman et al. 2004). Histopathologically, this condition is characterized by increased melanin pigmentation of the basal cell layer of the surface epithelium with collections of incontinent melanin pigmentation within the superficial connective tissue and in scattered macrophages (Alawi 2013). Patient Management Diagnosis of smoker s melanosis is usually established by a positive history of tobacco use Fig. 27 Smokers melanosis appearing as diffuse faint brown pigmentation on the buccal mucosa (Photo courtesy: Professor Camile Farah, Perth Oral Medicine & Dental Sleep Centre, Perth, WA, Australia) correlated with characteristic physical findings on clinical examination. If the lesion is present in an unexpected location and/or unusual changes are observed, such as surface elevation and/or increased melanin deposition, biopsy should be considered (Kauzman et al. 2004). If only one mucosal site is affected, melanoma should be considered in the differential diagnosis as it can also present as diffuse patchy pigmentation, and tissue biopsy is warranted (Alawi 2013). Other causes of diffuse melanin pigmentation, such as those described elsewhere in this chapter, should be excluded. Cessation of smoking habits results in gradual resolution of the lesions attributed to smoker s melanosis, typically within a 3-year period (Kauzman et al. 2004; Tarakji et al. 2014). No additional treatment is recommended as smoker s melanosis is not considered a preneoplastic condition (Alawi 2013).

18 18 E.T. Stoopler and F. Alawi Post-inflammatory (Inflammatory) Hyperpigmentation Epidemiology Post-inflammatory (inflammatory) hyperpigmentation is a condition characterized by pigment deposition in area(s) subjected to inflammation or previous injury that is more commonly observed in dark-complexioned individuals (Alawi 2013). Etiology The etiology of post-inflammatory (inflammatory) hyperpigmentation has not been determined (Gondak et al. 2012; Tarakji et al. 2014). Pathophysiology Inflammatory conditions, such as lichen planus, cause perturbation of epithelial melanocytes, resulting in increased melanin deposition in affected areas (Kauzman et al. 2004). Fig. 28 Post-inflammatory (inflammatory) pigmentation associated with lichenoid lesions on the buccal mucosa 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 previous trauma (Alawi 2013). In rare cases, the pigmentation 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 features (Alawi 2013). Patient Management Treatment is directed toward managing the underlying inflammatory condition when symptomatic, typically with topical corticosteroids. Pigmentation may or may not resolve with resolution of the lichenoid inflammation, and if it does, it may take several months to fade (Alawi 2013). Fig. 29 Post-inflammatory pigmentation on the left buccal mucosa in a patient with mild oral lichen planus (Photo courtesy: Professor Camile Farah, Perth Oral Medicine & Dental Sleep Centre, Perth, WA, Australia)

19 Pigmented Lesions of the Oral Mucosa 19 Laugier-Hunziker Pigmentation Epidemiology Laugier-Hunziker pigmentation (Laugier-Hunziker syndrome, Laugier-Hunziker-Baran syndrome) is characterized by acquired melanotic pigmentation of the labial and buccal mucosa (Alawi 2013; Yago et al. 2008). This is considered a rare condition that usually begins in the third to fifth decade of life with an overall female-male ratio of 2:1 (Nikitakis and Koumaki 2013;Yagoetal.2008). This condition has been reported in individuals in North America, Europe, and Asia and has been more commonly observed in Caucasian or light-skinned individuals (Yago et al. 2008). Etiology While the etiology of Laugier-Hunziker pigmentation is unknown, hormonal or genetic roles have not been associated with this condition (Alawi 2013; Fernandes et al. 2015; Nikitakis and Koumaki 2013). Pathophysiology The precise pathophysiologic mechanism of Laugier-Hunziker pigmentation is unclear, but it is considered an acquired pigmentation disorder that results from increased basal keratinocyte melanin without an increase in melanocytes (Nikitakis and Koumaki 2013). Clinical-Pathologic Features Multifocal, macular hyperpigmentation of the oral mucosa and lips is characteristic of Laugier- Hunziker pigmentation (Alawi 2013; Nikitakis and Koumaki 2013). Lesions may be solitary or 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 palate, and gingiva (Nikitakis and Koumaki 2013). Melanotic longitudinal streaks in the nails without associated nail dystrophy are frequently associated with oral pigmentation (Alawi 2013; Nikitakis and Koumaki 2013; Yago et al. 2008). Up to 60% of affected patients have nail involvement with fingernails more commonly affected than toenails (Fernandes et al. 2015). Similar lesions may be observed on other cutaneous surfaces, such as the facial skin and abdomen, and other mucosal surfaces, including the esophagus, conjunctiva, and anogenital mucosa (Alawi 2013; Nikitakis and Koumaki 2013). Typical histologic findings associated with Laugier-Hunziker pigmentation include increased basal keratinocyte melanin without an increase in number of melanocytes, melanin incontinence, and epithelial acanthosis in the absence of rete ridges or inflammation (Nikitakis and Koumaki 2013). Patient Management Treatment for this condition is typically not indicated unless there is an esthetic and/or psychological concern (Nikitakis and Koumaki 2013). Laser therapy and cryotherapy have been used to remove pigmentation, but recurrence is possible (Nikitakis and Koumaki 2013). It is important to consider systemic etiologies in the differential diagnosis of Laugier-Hunziker pigmentation, such as Addison disease and Peutz-Jeghers syndrome, as these conditions are also characterized by multiple oral mucosal macules (Nikitakis and Koumaki 2013). A thorough medical, social, and family history, in addition to a complete review of systems, are important in rendering an accurate diagnosis and appropriate referral to medical specialists, if necessary. Biopsy may be considered to confirm the clinical diagnosis and rule out other sources of oral pigmentation. Laugier-Hunziker pigmentation is a diagnosis of exclusion after all other potential sources for pigmentation have been eliminated as an etiology for the condition (Alawi 2013). Laugier-Hunziker pigmentation is not associated with malignant predisposition (Fernandes et al. 2015; Rangwala et al. 2010; Yagoetal.2008). Pigmentation Associated with Systemic or Genetic Disorders Adrenal Insufficiency (Addison Disease) Epidemiology Adrenal insufficiency is a potentially lifethreatening endocrinopathy that is characterized by diminished production of glucocorticoids

20 20 E.T. Stoopler and F. Alawi (cortisol) with or without a concomitant deficiency in mineralocorticoid and adrenal androgen levels (Naziat and Grossman 2000). Dysfunction in the hypothalamus-pituitary-adrenal gland axis gives rise to adrenal insufficiency. Primary, secondary, and tertiary forms of adrenal insufficiency are dependent upon the anatomic site of origin precipitating the dysfunction. An estimated new cases of primary adrenal insufficiency develop per million people per year (Charmandari et al. 2014). In contrast, secondary adrenal insufficiency is more common than the primary disease with an estimated prevalence of per million people. Overall, the prevalence of Addison disease in Caucasians is estimated to be between 1 in ,000 in the United States and Europe (Naziat and Grossman 2000). Primary adrenal insufficiency manifests more frequently in females than males and often between the ages of 30 and 50. Secondary disease is also more common in females but is usually diagnosed later in life. While the prevalence of oral mucosal hyperpigmentation (OMH) associated with adrenal insufficiency is not known, OMH is observed only in primary disease states. Etiology The hypothalamus-pituitary-adrenal gland axis is tightly coordinated to ensure glucocorticoid homeostasis (Charmandari et al. 2014). The hypothalamus produces corticotropin-releasing hormone (CRH) and vasopressin. These hormones act synergistically on the pituitary gland to activate pro-opiomelanocortin (POMC) gene expression (Anderson et al. 2016). The corresponding 241 amino acid POMC polypeptide then undergoes an array of posttranslational modifications to yield several biologically distinct hormone peptides. These include adrenocorticotropic hormone (ACTH); α-, β-, and γ-melanotropins (also known as melanocyte stimulating hormone), respectively, β- and γ-lipotropins; β-endorphin; and metenkephalin (Anderson et al. 2016). ACTH is secreted into the circulation and binds to receptors in the adrenal cortex to stimulate glucocorticoid production and release. Once serum cortisol levels are stabilized, ACTH and CRH synthesis are inhibited through an intricate negative feedback mechanism. When reduced cortisol levels are sensed by the hypothalamus, the CRH-POMC-ACTHcortisol signaling cascade is reactivated. OMH is observed only in primary adrenal insufficiency (Charmandari et al. 2014). The constitutively low cortisol levels stimulate persistent POMC production to yield high levels of ACTH. Since the defective adrenal glands are unable to sufficiently respond to ACTH, the signaling cascade remains active. In conjunction with ACTH overproduction, α-msh levels are also increased in parallel. α-msh is a short peptide encoded within the ACTH peptide and generated via posttranslational cleavage (Anderson et al. 2016). Since α-msh is a potent stimulator of melanogenesis, this triggers the mucocutaneous pigmentation observed in primary adrenal insufficiency (Anderson et al. 2016; Feller et al. 2014b). ACTH and α-msh levels are reduced in secondary and tertiary adrenal insufficiency (Charmandari et al. 2014). Thus, the pigmentation does not occur in these forms of the disease. Pathophysiology Primary adrenal insufficiency is caused by adrenocortical disease. While the most common cause is autoimmune adrenalitis, other conditions such as cancer, infection, and hemorrhagic infarction can also directly damage the adrenal glands (Charmandari et al. 2014). Several genetic disorders may lead to congenital defects in adrenal gland structure and function. Other genetic diseases may affect sensitivity of the glands to ACTH, limit glucocorticoid synthesis, or accelerate cortisol metabolism. A number of medications can also limit glucocorticoid biosynthesis or accelerate cortisol metabolism (Michels and Michels 2014). Examples include phenobarbital and phenytoin which activate cytochrome P450 enzymes thereby stimulating glucocorticoid metabolism. The antimycotic fluconazole and ketoconazole reduce cortisol synthesis by inhibiting mitochondrial cytochrome P450 enzymes. In rare instances, the use of the tyrosine kinase inhibitors imatinib, saracatinib, and sunitinib has been associated with adrenal insufficiency and other endocrinopathies, including

21 Pigmented Lesions of the Oral Mucosa 21 Fig. 30 Oral mucosal pigmentation in a Caucasian patient with adrenal insufficiency. Melanin pigmentation is noted in the basal epithelial layer. This patient was diagnosed with Addison disease 2 months after he developed diffuse oral pigmentation and histopathologic evaluation of the biopsy tissue (hematoxylin and eosin, 200) Patient Management Treatment of adrenal insufficiency should be implemented as soon as a deficiency state is recognized. 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 recommended for patients who are unable to tolerate oral medications. Mineralocorticoid- and androgen-replacement therapy is also frequently necessary. Once serum cortisol levels normalize, the pigmentation may eventually resolve. hypothyroidism and alterations of glucose metabolism (Lodish 2013). Secondary insufficiency is caused by surgical trauma and neoplastic (e.g., pituitary adenoma) or genetic disorders (e.g., Prader-Willi syndrome) affecting the anterior lobe of the pituitary gland resulting in reduced secretion of ACTH (Charmandari et al. 2014). Tertiary adrenal insufficiency is usually caused by chronic exposure to exogenous glucocorticoids resulting in decreased secretion of CRH and/or vasopressin from the hypothalamus. Clinical-Pathologic Features The onset of primary adrenal insufficiency may be insidious and nonspecific. The first sign of disease may be diffuse bronzing of the skin with or without patchy OMH (Fig. 30). With persistence of the cortisol deficiency, the clinical signs and symptoms may become generalized. Complications may include weakness and fatigue, gastrointestinal complaints, orthostatic hypotension, musculoskeletal pain, anorexia, salt craving, and behavioral changes (Charmandari et al. 2014). While the hyperpigmentation is not clinically significant, its sudden appearance may necessitate evaluation of the patient for Addison disease. Cushing Disease Cushing syndrome is a potentially lifethreatening disease caused by prolonged exposure to hypercortisolism that may arise from exogenous or endogenous causes (Sharma et al. 2015). Overadministration of glucocorticoids such as dexamethasone and prednisone, or drugs that reduce the clearance of synthetic glucocorticoids, including itraconazole, are the major cause of Cushing syndrome. Endogenous Cushing syndrome is classified into ACTH-dependent and ACTH-independent variants (Lacroix et al. 2015). Cushing disease is the most common cause of ACTH-dependent endogenous Cushing syndrome (Sharma et al. 2015). Cushing disease is primarily induced by an ACTH-secreting pituitary adenoma. Other ACTH-dependent forms of Cushing syndrome may arise from ectopic ACTH- or, rarely, CRH-secreting tumors originating in other anatomic sites. ACTHindependent Cushing syndrome develops secondary to functional adrenal neoplasms (Lacroix et al. 2015). Oral melanocytic pigmentation only develops in ACTH-dependent Cushing syndrome. The ensuing discussion will focus on Cushing disease.

22 22 E.T. Stoopler and F. Alawi Epidemiology The estimated incidence rate of endogenous Cushing syndrome is per million populations per year, with a standardized mortality ratio of almost four (Sharma et al. 2015). It is possible that incidence rates of endogenous Cushing syndrome are underestimated. Studies of patients with uncontrolled diabetes, hypertension, or early-onset osteoporosis have revealed previously undiagnosed Cushing syndrome in a subset of cases (De Leo et al. 2012). Most patients die of disease within the first year after initial presentation. Even with appropriate treatment, the risk for disease-related morbidity and mortality remains significantly higher than that of the general population and may persist for several years after normalization of cortisol levels (Lonser et al. 2016). In particular, treated patients may retain a high risk for future development of diabetes, dyslipidemia, obesity, and neurocognitive and psychiatric disorders. Risk from death associated with cardiovascular complications also remains elevated. Cushing disease accounts for 65 80% of all ACTH-dependent forms of Cushing syndrome (Lacroix et al. 2015). It has an estimated prevalence of 39.1 per million persons. Overall, females are more commonly afflicted than males; ratios of 3 5:1 have been reported. Although Cushing disease can present at any age, most cases are diagnosed in the fourth decade, with females frequently being diagnosed at an earlier age than males. Etiology Cushing disease is usually caused by a primary pituitary pathology usually an ACTH-secreting adenoma (Lonser et al. 2016). In rare instances, tumors in other anatomic sites can also precipitate ACTH-dependent ectopic Cushing syndrome. These include small cell neuroendocrine and carcinoid tumors of the lung and other organs, islet-cell tumors of the pancreas, medullary thyroid carcinoma, pheochromocytomas, and thymomas. Hyperpigmentation may be observed in any ACTH-dependent form of Cushing syndrome. Pathophysiology Excessive and pathologically constitutive secretion of ACTH results in persistent stimulation of the adrenal glands to release cortisol (Lonser et al. 2016). Since the pituitary neoplasm is resistant to the negative feedback control mechanisms, ACTH and cortisol levels remain high. The mucocutaneous pigmentation develops via the same mechanism as that described for primary adrenal insufficiency, i.e., α-msh levels increase in parallel with ACTH. In rare instances, Cushing disease may also be a manifestation of genetic diseases, including multiple endocrine neoplasia type 1 (MEN1) and multiple endocrine neoplasia type 4 (MEN4) (Schernthaner-Reiter et al. 2016). Germline mutations of the MEN1 and CDKN1B genes precipitate MEN1 and MEN4 syndromes, respectively (Schernthaner-Reiter et al. 2016). Germline mutations in the aryl-hydrocarbon receptor-interacting protein predispose to pituitary adenomas (pituitary adenoma predisposition syndrome) (Lloyd and Grossman 2014). Cushing disease may also manifest in Carney complex resulting from pituitary adenoma harboring a germline mutation in PRKAR1A (Schernthaner- Reiter et al. 2016). Similarly, somatic mutations of GNAS (G-protein-coupled receptor alpha subunit [Gsα], which activates adenylate cyclase) also predispose to pituitary adenomas (Brown et al. 2010). GNAS mutations are associated with McCune-Albright syndrome. Patients with this disorder also develop pigmented macular lesions of the skin known as café-au-lait spots. Café-au-lait pigmentation does not occur within the oral cavity. Clinical-Pathologic Features Oral mucosal and/or cutaneous hyperpigmentation may be one of the earliest signs of Cushing disease (Lacroix et al. 2015) (Fig. 31). More significantly, prolonged exposure to hypercortisolism results in an array of variably severe and potentially life-threatening complications. Most commonly these include but are not limited to obesity, diabetes mellitus, moon facies, hypertension, amenorrhea, osteoporosis, hirsutism, abdominal striae, dorsocervical fat pads ( buffalo

23 Pigmented Lesions of the Oral Mucosa 23 Human Immunodeficiency Virus (HIV): Associated Pigmentation Fig. 31 Multifocal mucosal pigmentation on the hard palate (arrows) in a patient who was eventually diagnosed with Cushing syndrome hump ), cutaneous purpura, poor wound healing, muscular weakness, psychological, psychiatric and neurocognitive disturbances, immune suppression, male impotence, and female infertility (Lacroix et al. 2015). Patient Management There is no specific treatment for the pigmentation. Treatment of the underlying cause of Cushing disease usually surgical removal of the pituitary tumor often times has an immediate inhibitory effect on cortisol secretion (Lau et al. 2015). In cases where the tumor may be inoperable, radiation therapy may be employed, or the hypercortisolism may be treated medicinally. Medical therapies can target the pituitary gland, the adrenal gland, or the peripheral tissues. Pituitary targeting is designed to inhibit ACTH synthesis and secretion. Cabergoline (dopamine 2 receptor agonist) and pasireotide (somatostatin 5 receptor agonist) are two drugs that are currently available for patients who are poor surgical candidates or who failed surgical therapy (Lau et al. 2015). Steroidogenic inhibitors including ketoconazole may be used to inhibit cortisol synthesis. Mifepristone is a progesterone receptor antagonist that also inhibits glucocorticoid receptor activity. Mifepristone reduces the hyperglycemia associated with Cushing disease. Resolution of the biochemical defect will result in normalization of ACTH and α-msh levels. Over time, the pigmentation may eventually resolve. Epidemiology OMH is a recognized occurrence in HIV-seropositive 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/mm 3 or less (Feller et al. 2014a). A potential relationship between viral load and OMH remains uncertain. The overall prevalence of OMH is not known. However, there are geographic and ethnic differences that could reflect specific characteristics of the HIV infection, access to appropriate treatment, and/or administration of specific drug regimens. In South Africa, Venezuela, and India, % of HIV-seropositive patients were identified with OMH (Bravo et al. 2006; Chandran et al. 2016; Feller et al. 2014a). In contrast, in Greece and Italy OMH accounts for less than 2% and 7%, respectively, of all examined patients. In general, mucosal pigmentation is usually more prominent in darker-skinned individuals and may be more prevalent in females than in males (Feller et al. 2014a). In at least one study, HIV-associated OMH was also significantly associated with smoking (Chandran et al. 2016). Etiology The etiology of HIV/AIDS-associated pigmentation is multifactorial. There is currently no evidence HIV can directly infect or activate melanocytes (Feller et al. 2014a). Instead, HIV-induced cytokine dysregulation may induce OMH. Nonspecific, generalized oral mucosal inflammation could also be contributory. Pro-inflammatory cytokines including interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-α are known to regulate melanocytes and melanogenesis (Feller et al. 2014b). Constitutive upregulation of these and other pro-inflammatory mediators may stimulate production of α-msh thereby leading to the pigmentation. HIV-induced cytokine dysregulation typically parallels decreasing CD4 + T-cell counts (Feller et al. 2014a).

24 24 E.T. Stoopler and F. Alawi More commonly, OMH may arise in response to treatment with a number of different medications frequently used to treat HIV/AIDS and its associated complications; zidovudine (azidothymidine [AZT]; nucleoside reverse transcriptase inhibitor) is just one example (Feller et al. 2014a). The pigment frequently appears within the first few weeks after initiation of the therapy. When the drug is withdrawn, the pigment usually diminishes. OMH is significantly more common in HIV-seropositive patients treated with antiretroviral therapy (ART) than in ART-naïve individuals. Primary or secondary adrenocortical dysfunction may occur in as many as 20% of HIV patients (Hruz 2014). This may be due to HIV-associated viral or mycobacterial infections of the adrenal gland or by medications used to treat the disease. Ritonavir (protease inhibitor) in combination with exogenous steroids is known to induce adrenal insufficiency which, in turn, may induce the pigmentation (Wood et al. 2015). Pathophysiology The pathogenesis of HIV-associated pigmentation varies depending on the etiologic agent. Similar to other forms of OMH, the pigmentation is usually the result of increased melanogenesis without a change in melanocyte number. The pigment is concentrated within the basal layer of the stratified squamous epithelium and accompanied by melanin incontinence within the papillary lamina propria (Feller et al. 2014a). The pigment is often easily visualized in biopsy tissue with routine light microscopy. HIV-induced cytokine dysregulation and AZT and other medications may also induce pigmentation by stimulating melanocytic hyperplasia accompanied by an increase in melanin synthesis. Clinical-Pathologic Features The pigmentation may manifest as multiple discrete light to dark brown macules or as patchy and diffuse. The coloration may appear anywhere within the oral cavity, but the gingiva tends to be the most commonly affected site. In darkerskinned individuals, differentiating HIV-associated pigment from physiologic pigmentation may be difficult. The appearance, extent, and intensity of OMH is also similar to that observed in other disorders known to induce mucocutaneous pigmentation. The diagnosis of HIV-associated pigmentation is rendered if the pigment initially appears or becomes exacerbated after the diagnosis of HIV infection or following the initiation of therapy (Feller et al. 2014a). Patient Management Apart from possible esthetic concerns, there does not appear any clinical significance attributable to HIV-associated OMH. However, new onset oral pigmentation in an individual deemed potentially high risk for HIV infection, including intravenous drug users, should prompt an evaluation for possible infection. Peutz-Jeghers Syndrome Peutz-Jeghers syndrome (PJS) is an autosomal dominant disorder associated with oral and perioral melanocytic pigmentation, benign hamartomatous polyps of the gastrointestinal tract, and increased risk for developing malignancies of the gastrointestinal tract, breast, uterine cervix, ovary, pancreas, and other anatomic sites (Riegert-Johnson et al. 2009). The risk is estimated to be 18-fold higher than that of the general population. The hyperpigmentation often manifests early in life and may be the first sign of disease in some patients. Epidemiology Since PJS is a rare disorder, reliable estimates of incidence and prevalence are lacking. Nonetheless, PJS has an estimated incidence of 1 in ,000 live births without gender or racial predilection (Riegert-Johnson et al. 2009). Mortality associated with PJS is usually cancer related. Etiology Approximately 75% of all PJS patients harbor a germline mutation in the SKT11 (LKB1) gene located on chromosome 19p13.3 (Meserve and Nucci 2016). The remaining patients do not have

25 Pigmented Lesions of the Oral Mucosa 25 Fig. 32 Perioral melanosis associated with Peutz-Jeghers syndrome known STK11 mutations; the genetic cause of these patients disease remains undetermined. Mutations in STK11-interacting proteins have not yet been found in these latter patients. Thus, it has been suggested that these patients may have large STK11 gene rearrangements that cannot be identified by routine molecular testing (Meserve and Nucci 2016). Pathophysiology STK11 is serine-threonine kinase that directs energy sensing and nutrient metabolism through activation of an array of downstream factors (Shorning and Clarke 2016). Together, STK11 and its phosphorylated substrates help to regulate cellular metabolism, proliferation, polarity, and differentiation by maintaining and monitoring cellular energy homeostasis. STK11 also contributes to genomic stability by participating in DNA double-strand break repair. It is apparent that STK11 plays an important role in melanocyte biology since the mucocutaneous pigmentation is observed in essentially all patients with PJS (Ponti et al. 2016). Moreover, the hyperpigmentation can be observed in STK11-deficient murine models (Meserve and Nucci 2016). Nonetheless, the mechanisms by which loss of STK11 function induces hyperpigmentation remain unclear. Clinical-Pathologic Features PJS is commonly associated with multiple melanotic macules of the lips accompanied by diffuse freckling of the perioral skin (Ponti et al. 2016) (Fig. 32). The pigmented macules may coalesce to produce broader areas of pigmentation. Less commonly, 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 pigmentation may spontaneously resolve with age. A biopsy of a pigmented lesion usually reveals nonspecific histopathology (Ponti et al. 2016). There is increased melanin pigmentation within the basal epithelial layer and melanin incontinence within the papillary lamina propria. There may also be evidence of melanocytic hyperplasia. Note that while highly characteristic, the pattern of labial and perioral pigmentation is not pathognomonic for PJS. Laugier-Hunziker pigmentation is an acquired and idiopathic form of pigmentation that frequently mimics PJS and should be considered in the differential diagnosis (Alawi 2013). However, Laugier-Hunziker pigmentation typically manifests during adulthood and may be accompanied by pigmentation of the nails. Patients with Laugier-Hunziker pigmentation do not exhibit STK11 mutations, and they do not manifest with gastrointestinal polyps. Apart from the gastrointestinal polyps and cancer, other systemic complications may include intussusception, rectal bleeding, iron deficiency anemia, and development of ovarian cysts (Riegert-Johnson et al. 2009). Patient Management The development of labial and perioral pigmentation early in life should prompt genetic testing for PJS (Meserve and Nucci 2016). In patients with a known family history or in newly diagnosed patients, surveillance strategies should be designed to ensure continuous and lifelong clinical monitoring. Surgical treatment may be needed to remove potentially obstructive gastrointestinal polyps. Iron supplementation may be necessary for a subset of patients who are anemic. Prognosis is primarily related to the occurrence of cancer (Meserve and Nucci 2016). The pigmentation is

26 26 E.T. Stoopler and F. Alawi not symptomatic and does not require treatment unless there is an esthetic concern. Exogenous Causes of Clinical Pigmentation Tattoos: Amalgam, Graphite, and Ornamental The most common nonphysiologic source of oral mucosal coloration is exogenous and not endogenous in origin (Alawi 2013). Amalgam tattoos are the most common cause of oral pigmentation (Alawi 2013). They result from the iatrogenic mucosal implantation of amalgam particles usually during the course of a dental procedure. Amalgam tattoos are macular, usually small and frequently identified in close proximity to amalgam-restored teeth or in areas where such teeth were previously present (Figs. 33a c, 34, 35, and 36). Amalgam tattoos may be identified in any oral location, but the gingiva and alveolar mucosa are most commonly affected. While an amalgam tattoo may be blue gray to black in color, and thus the mucosa may appear clinically pigmented, the mucosa is not actually pigmented (Alawi 2013). The coloration is due to the visualization of metallic particles embedded within the lamina propria and/or submucosa. Similarly, graphite tattoos may appear clinically identical to amalgam tattoos (Fig. 37). Graphite tattoos are caused by the mucosal implantation of graphite particles typically originating from the tip of a pencil (Alawi 2013). These tattoos are usually the result of accidental trauma. Ornamental or intentional oral mucosal tattoos have long been a custom in some parts of the world, including within specific African tribal communities, which has been described previously in this chapter (Gondak et al. 2012). The tattoo ink is usually plant based and may be combined with other carbon-based substances such as burnt wood, plastic, India ink, or even pen ink. Ornamental tattooing is a growing trend in other parts of the world, including Eastern European and Western countries (Fig. 38). Fig. 33 Amalgam tattoo appearing clinically as a black pigmented lesion on the labial gingiva of the tooth 16 (a). Same lesion noted on multislice CT sagittal (b) and axial (c) views confirming presence of amalgam particles (Photo courtesy: Professor Camile Farah, Perth Oral Medicine & Dental Sleep Centre, Perth, WA, Australia)

27 Pigmented Lesions of the Oral Mucosa 27 Fig. 34 Amalgam tattoo appearing clinically as black 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. 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 Medicine & Dental Sleep Centre, Perth, WA, Australia) Fig. 35 Biopsy-proven amalgam tattoo appearing clinically 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 heavily restored primary dentition (Photo courtesy: Professor Camile Farah, Perth Oral Medicine & Dental Sleep Centre, Perth, WA, Australia) Fig. 37 Biopsy-proven graphite tattoo in a 63-year-old female appearing clinically as a gray pigmented lesion on the gingiva (Photo courtesy: Professor Camile Farah, Perth Oral Medicine & Dental Sleep Centre, Perth, WA Australia)

28 28 E.T. Stoopler and F. Alawi Fig. 38 Ornamental ink tattooing involving the mandibular labial mucosa in a female patient which reads In My Stars (Photo courtesy: Clinical Associate Professor Ramesh Balasubramaniam, Oral Health Centre of Western Australia, School of Dentistry, University of Western Australia, Perth, WA, Australia) For focal areas of discoloration, a biopsy diagnosis is first warranted since mucosal tattoos may be difficult to reliably differentiate from benign and malignant melanocytic and/or vascular pathologies (Alawi 2013). In instances where metallic amalgam particles may be evident on a radiograph, this may preclude the need for biopsy diagnosis. After histopathologic diagnosis, no additional intervention is needed. While the esthetic concerns associated with amalgam, graphite, and ornamental tattooing may be significant for some individuals, treatment is not indicated. However, if treatment is requested, low-energy lasers can be used to remove the tattoos (Yilmaz et al. 2010). Subepithelial connective tissue grafts followed by laser de-epithelialization or gingivoplasty have also been used with success (Campbell and Deas 2009; Thumbigere-Math and Johnson 2014). Alternatively, simple cold steel surgical excision of affected tissues is a straightforward approach. Metal-induced Discoloration Chronic exposure to various metals is known to induce discoloration but not true pigmentation of the oral mucosa (Alawi 2013; Hassona et al. 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 occupational exposure. In most cases, the discoloration appears as a black-blue line that follows the outlines of the marginal gingiva (Alawi 2013; Hassona et al. 2016). This is known as a Burton or Burtonian line in individuals with chronic lead poisoning (Pearce 2007). Similar to an amalgam tattoo, a Burton line is not true pigmentation. Instead, a chemical reaction occurs between sulfur ions released by the regional oral flora and the circulating lead. This results in the deposition of lead sulfide within the marginal gingiva leading to the discoloration. Mercury lines and bismuth lines develop via similar types of chemical reactions with compounds released by oral bacteria. Mucocutaneous argyria is due to the accumulation of silver metal or silver sulfide within the lamina propria and submucosa and often manifests as generally diffuse bluish mucosal discoloration (Kim et al. 2009). Identifying and eliminating the source of the toxicity is critical to ensure there are no longlasting systemic and neurologic effects. Chelation therapy under professional supervision may be beneficial, but the extent of exposure and the specific type of metal toxicity dictates which chelating agent(s) will be used and the mode of administration (Caito and Aschner 2015). Succimer (2,3-dimercaptosuccinic acid [DMSA]) is an orally administered chelating agent typically used for lead, mercury, or arsenic poisoning. Intravenous dimercaprol can be used in severe cases. Calcium-disodium ethylenediaminetetraacetic acid (EDTA) is also recommended for lead poisoning. A monoisoamyl ester derivative of DMSA may be more effective at chelating mercury than succimer. It should be noted that while succimer has a limited side-effect profile, intravenously administered chelating agents can be associated with a wide array of serious adverse effects, including renal failure, seizures, coma, and even death (Caito and Aschner 2015).