5
Pigmented Lesions of the Oral Mucosa
Alfredo Aguirre, DDS, MS
Faizan Alawi, DDS
Jose Luis Tapia, DDS, MS
Healthy oral soft tissue presents a typical pink to red hue that reflects the degree of keratinization, quantity and activity of melanocytes, vascularization, and type of submucosal tissue of distinct topographic areas.1 Although oral and perioral pigmentation may be physiologic in nature, particularly in individuals with a darker complexion, throughout the course of disease it is possible for the oral mucosa and perioral tissues to assume a variety of discolorations, including brown, blue, gray, and black. Such color changes are often attributed to the deposition, production, or increased accumulation of various endogenous or exogenous pigmented substances. However, although an area may appear pigmented, the discoloration may not be related to actual pigment, but rather to the deposition or accumulation of organic or inorganic substances, including various metals and drug metabolites.2
Hemoglobin, hemosiderin, and melanin represent the most common endogenous sources of mucosal color change (Table 5‐1). A submucosal collection of hemoglobin or hemosiderin, produced by extravasation and/or lysis of red blood cells, may impart a red, blue, or brown ephemeral appearance to the oral mucosa. Melanin, which is synthesized by melanocytes and nevus cells, may appear as brown, blue, or black, depending on the amount of melanin and its spatial location within the tissue (i.e., superficial vs. deep).
Table 5‐1 Common causes of endogenous oral and perioral discoloration.
| Source | Etiology | Examples of Associated Lesion, Condition, or Disease |
|---|---|---|
| Vascular | Developmental Hamartomatous Neoplastic Genetic Autoimmune |
Varix Hemangioma Lymphangioma Angiosarcoma Kaposi’s sarcoma Hereditary hemorrhagic telangiectasia CREST syndrome |
| Extravasated hemorrhage, hemosiderin | Trauma Idiopathic Genetic Inflammatory Autoimmune |
Hematoma Ecchymosis Purpura Petechiae Vasculitis Hemochromatosis |
| Melanin | Physiologic Developmental Idiopathic Neoplastic Reactive Drugs Hormones Genetic Autoimmune Infectious |
Melanotic macule Ephelis Actinic lentigo Melanocytic nevus Malignant melanoma Physiologic pigmentation Chloroquine‐induced pigmentation Imatinib‐induced pigmentation Lichen planus pigmentosus Laugier–Hunziker syndrome Smoker’s melanosis Oral submucous fibrosis Peutz–Jeghers syndrome Adrenal insufficiency Cushing’s syndrome HIV/AIDS |
| Bilirubin | Trauma Alcohol Infection Neoplasia Genetic Autoimmune |
Jaundice |
Exogenous pigmentations are usually associated with traumatic or iatrogenic events resulting in the deposition of foreign material directly into the mucosal tissues (Table 5‐2).3 In some cases, the substances may be ingested, absorbed, and distributed hematogenously into connective tissues, particularly in areas subject to chronic inflammation, such as the gingiva. In other instances, these ingested substances can stimulate melanin production, thus precipitating a color change. Chromogenic bacteria can produce discoloration of the dorsal tongue. Certain foods, drinks, and confectionery can also result in exogenous pigmentation that, in most cases, is reversible.
Clinically, oral pigmentations can range from a solitary macule to large patches and broad, diffuse tumefactions. The specific hue, duration, location, number, distribution, size, and shape of the pigmented lesion(s) may be of diagnostic importance. In addition, recording extensive social, family, medical, and dental histories, various diagnostic procedures (e.g., colonoscopy), and laboratory tests (including biopsy) may be necessary. Thus, an understanding of the various disorders and substances that can contribute to oral and perioral pigmentation is essential for the appropriate evaluation, diagnosis, and management of the patient.
Table 5‐3 lists additional lesions that may be associated with oral mucosal discoloration. Each of these lesions is discussed in more detail elsewhere in this textbook. Similarly, vascular lesions such as hemangioma, lymphangioma, angiosarcoma, and Kaposi’s sarcoma, which are frequently considered in the differential diagnosis of macular and mass‐forming pigmented lesions, are shown in Table 5.1, but otherwise excluded from this chapter.
ENDOGENOUS PIGMENTATION
Melanin is the pigment derivative of tyrosine and is synthesized by melanocytes, which typically reside in the basal cell layer of the epithelium.4 Investigations into normal melanocyte homeostasis led to the discovery that keratinocytes control melanocytic growth.5 Yet the mechanisms by which melanocytes are stimulated to undergo cell division remain poorly understood. Their presence in the skin is thought to protect against the damaging effects of actinic irradiation. They also act as scavengers, protecting against cytotoxic intermediates.6 However, the role of melanocytes in oral epithelium is unclear.
Melanin is not commonly observed in routine biopsies of the oral mucosa, unless the tissues were obtained from non‐Caucasoid individuals. Oral melanocytic pigmentation in Caucasians is almost always considered pathologic in origin, although the pathology or pigment itself may be of no clinical significance.
Melanin is synthesized within specialized structures known as melanosomes. It is composed of eumelanin, a brown‐black pigment, and pheomelanin, a pigment of red‐yellow color.4 The term melanosis is used to describe diffuse hyperpigmentation. Cutaneous overproduction of melanin may be associated with a variety of mechanisms, but most commonly with increased sun exposure. However, intraorally, hyperpigmentation is more typically a consequence of physiologic, idiopathic sources, neoplasia, medications, high serum concentrations of pituitary adrenocorticotropic hormone (ACTH), postinflammatory changes, and genetic or autoimmune disorders. Therefore, the presence or absence of systemic signs and symptoms, including cutaneous hyperpigmentation, is of great importance to elucidate the genesis of oral pigmentations. If the etiology of the oral pigmentation cannot be clinically established, a tissue biopsy is warranted for definitive diagnosis. This is critical, because malignant melanoma may present with a deceptively benign clinical appearance.
Table 5‐2 Sources of exogenous oral and perioral pigmentation.
Source: Based on Muller S. Melanin‐associated pigmented lesions of the oral mucosa: presentation, differential diagnosis, and treatment. Dermatol Ther. 2010(3);23:220–9.
| Source | Etiology | Examples of Associated Lesion, Condition, or Disease |
|---|---|---|
| Metal | Iatrogenic Medications Environment |
Amalgam tattoo Chrysiasis Black tongue Heavy metal pigmentation |
| Graphite/ink | Trauma Factitious Tribal customs |
Graphite tattoo |
| Bacteria | Poor oral hygiene Antibiotics |
Hairy tongue |
| Drug complexes | Medications | Minocycline‐induced pigmentation |
| Plant derivatives | Factitious Tribal customs |
Ornamental tattoo Orange mouth |
Table 5‐3 Miscellaneous lesions that may be associated with oral mucosal discoloration.
| Lesion | Color |
|---|---|
| Pyogenic granuloma | Red, blue |
| Peripheral ossifying fibroma | Red, blue |
| Peripheral giant cell granuloma | Red, blue |
| Mucocele | Blue |
| Mucoepidermoid carcinoma | Blue |
| Acinic cell carcinoma | Blue |
| Lymphoma | Blue, purple |
| Vascular leiomyoma | Red, blue |
| Metastatic cancer | Red, blue |
| Fordyce granule | Yellow |
| Lipoma | Yellow |
| Granular cell tumor | Yellow |
In addition to biopsy and histologic study, various laboratory and clinical tests, including diascopy, radiography, and blood tests, may be necessary for the definitive diagnosis of oral pigmentations. Recently, two noninvasive tests, which were originally developed to study cutaneous pigmentation, have been applied to evaluate oral melanosis. The first, dermoscopy (also known as epiluminescence microscopy), uses a handheld surface microscope, incident light, and oil immersion. This technique has been successfully used for the evaluation of selected oral pigmented lesions.7 The second, reflectance confocal microscopy (RCM), allows the in vivo microscopic visualization of the skin and mucosa, which provides high‐resolution horizontal views with an approximate depth of 200–300 μm.8 This procedure can assist in the diagnosis and management of benign and malignant pigmented lesions of the lips.9 Because prospective and controlled studies detailing the predictive value and efficacy of dermoscopy and RCM for the diagnosis of oral pigmented lesions have not been performed, the practitioner should be wary of their use in common clinical dental practice.
In summary, melanin pigmentation may be physiologic or pathologic, and may clinically present with focal, multifocal, or diffuse patterns. Figures 5‐1 and 5‐2 show algorithms that can assist the clinician in associating these patterns with selected pigmented conditions.
Figure 5‐1 Focal pigmented lesions. Algorithm illustrating clinical procedures needed to segregate and diagnose common focal pigmented lesions.
Figure 5‐2 Multifocal and diffuse pigmented lesions. Algorithm illustrating the clinical presentation of pigmented lesions with accompanying habits, endoscopic features, and systemic/laboratory findings that allow their segregation.
FOCAL MELANOCYTIC PIGMENTATION
Freckles/Ephelis
Freckles is the lay term for ephelis and lentigines, which are commonly occurring, asymptomatic, well‐circumscribed, tan‐ or brown‐colored macules often seen on sun‐exposed regions of the skin (Figure 5‐3). Ephelides are most commonly observed in light‐skinned individuals and are quite prevalent in red‐ or light blond‐haired individuals. Freckles are thought to be developmental in origin. A number of genes have been shown to participate in their formation.10
Ephelides are usually more abundant in number and darker in intensity during childhood and adolescence. They tend to become darker during periods of prolonged sun exposure (e.g., spring, summer) and fade during the autumn and winter months. However, the increase in pigmentation is solely related to an increase in melanin production without a concomitant increase in the number of melanocytes. With increasing age, the number of ephelides and color intensity tend to diminish. In contrast, the number of lentigines tends to increase. In general, no therapeutic intervention is required.
Oral/Labial Melanotic Macule
Etiology and Pathogenesis
The melanotic macule is a unique, benign, pigmented lesion that has no known dermal counterpart. Melanotic macules are the most common oral lesion of melanocytic origin. In one large‐scale retrospective study, melanotic macules made up over 85% of all solitary melanocytic lesions.11 Although the etiology remains elusive, trauma has been postulated to play a role. Sun exposure is not a precipitating factor.
Figure 5‐3 Ephelis of the lower vermilion border. Brown pigmented macule with circumscribed borders on the left lower vermilion border.
Clinical Features
Melanotic macules develop more frequently in females, usually in the lower lip (labial melanotic macule) and gingiva. However, any mucosal site may be affected. Although the lesion may develop at any age, it generally tends to present in adulthood. Congenital melanotic macules have been described, occurring primarily in the tongue.12 Overall, melanotic macules tend to be small (<1 cm), well‐circumscribed, oval or irregular in outline, and often uniformly pigmented (Figure 5‐4). Once the lesion reaches a certain size, it does not tend to enlarge further. Unlike an ephelis, a melanotic macule does not become darker with continued sun exposure. Overall, the oral melanotic macule is a relatively innocuous lesion, and in general will not recur following surgical removal. However, an apparent association between oral melanotic macule and melanoma has been documented.13
Pathology
Microscopically, melanotic macules are characterized by the presence of abundant melanin pigment in the basal cell layer without an associated increase in the number of melanocytes (Figure 5‐5). Pigmentation is often accentuated at the tips of the rete pegs, and melanin incontinence into the subjacent lamina propria is commonly encountered. Melanocytic hyperplasia is an ominous microscopic finding that may herald the development of malignant melanoma.
Differential Diagnosis
The differential diagnosis includes melanocytic nevus, malignant melanoma, amalgam tattoo, and focal ecchymosis. If such pigmented lesions are present after a two‐week period, ecchymosis can usually be ruled out.
Figure 5‐4 Melanotic macule of the lower labial mucosa.
Source: Courtesy of Dr. John Fantasia, North Shore‐LIJ Health System, LIJMC, New Hyde Park, NY, USA.
Figure 5‐5 Melanotic macule exhibiting increased melanin pigmentation within the basal cell layer and melanin incontinence (hematoxylin and eosin, ×400).
Source: Courtesy of Dr. John Fantasia, North Shore‐LIJ Health System, LIJMC, New Hyde Park, NY, USA.
Management
A biopsy specimen should be obtained to secure a definitive diagnosis. Once the microscopic diagnosis is obtained, no further treatment is necessary. Since oral mucosal malignant melanomas have no defining clinical characteristics, a biopsy of any persistent solitary pigmented lesion is always warranted.
Oral Melanoacanthoma
Etiology and Pathogenesis
Oral melanoacanthoma is an innocuous melanocytic lesion that may spontaneously resolve, with or without surgical intervention.14 Although the term melanoacanthoma may imply a neoplastic process, the oral lesion is actually reactive in nature. Most patients report a rapid onset, with acute trauma or a history of chronic irritation preceding the development of the lesion. A biopsy is always warranted to confirm the diagnosis, but once rendered, no further treatment is required. The biopsy procedure itself may lead to spontaneous regression of the lesion. If it has been identified, the underlying source of the irritation should be eliminated in order to minimize recurrence.
Clinical Features
Oral melanoacanthoma usually presents as a rapidly enlarging, ill‐defined, darkly pigmented flat or slightly elevated lesion with a predilection for black females. Although lesions may present over a wide age range, the majority occur between the third and fourth decades of life. Typically, melanoacanthoma presents as a solitary lesion; nevertheless, bilateral and multifocal lesions have been reported.15
Oral melanoacanthomas are generally asymptomatic; however, pain may be present.14 Although any mucosal surface may be involved, close to 50% of melanoacanthomas arise on the buccal mucosa.15 The size of the lesion is variable, ranging from small and localized to large, diffuse areas of involvement, measuring several centimeters in diameter. The borders are typically irregular in appearance, and the pigmentation may be uneven (Figure 5‐6).
Although there is a recognized cutaneous melanoacanthoma,16 it is clear that the similarities with oral melanoacanthoma lie solely in the nomenclature. Cutaneous melanoacanthoma represents a pigmented variant of seborrheic keratosis and typically occurs in older Caucasian patients. Dermatosis papulosa nigra is a relatively common facial condition that typically manifests in older black patients, often female, and represents multiple pigmented seborrheic keratoses.17 These small papules are often identified in the malar and preauricular regions of the face.
Figure 5‐6 Melanoacanthoma. Pigmented macule on the attached and marginal gingiva displaying irregular borders.
Source: Reproduced from Tapia JL, Quezada D, Gaitan L, et al. Gingival melanoacanthoma: case report and discussion of its clinical relevance. Quintessence Int. 2011;42(3):253–258, with permission from Quintessence International.
Pathology
Microscopically, oral melanoacanthomas are characterized by a proliferation of benign, dendritic melanocytes throughout the full thickness of an acanthotic and spongiotic epithelium (Figure 5‐7).14 A mild lymphocytic infiltrate with exocytosis is also characteristic. Occasional eosinophils may be observed.
Differential Diagnosis
Pigmented nevus, melanotic macule, and melanoma should be included in the differential diagnosis.
Management
A biopsy is warranted to obtain a definitive diagnosis. No further treatment is indicated.
Melanocytic Nevus
Etiology and Pathogenesis
Melanocytic nevi include a diverse group of clinically and/or microscopically distinct lesions.18 Unlike ephelides and melanotic macules, which result from an increase in melanin pigment synthesis, nevi arise as a consequence of melanocytic growth and proliferation.11 In the oral cavity, the intramucosal nevus is most frequently observed, followed by the common blue nevus.19 Compound nevi are less common, and the junctional nevus and combined nevus (a nevus composed of two different cell types) are infrequently identified. Rare reports of congenital nevus, Spitz nevus, balloon cell nevus, and the cellular, epithelioid, and plaque type variants of blue nevus have also been described. However, the list of morphologically distinct nevi continues to expand.
Figure 5‐7 Melanoacanthoma. Dendritic‐shaped, pigmented melanocytes (arrows) are noted throughout the full thickness of a spongiotic and acanthotic epithelium (hematoxylin‐eosin stain; ×400 original magnification).
Relatively little is known about the pathogenesis of the various melanocytic nevi. In fact, there is still debate as to whether “nevus cells” are a distinct cell type derived from the neural crest or if they are simply a unique or immature form of melanocyte.4 Nonetheless, the lesional nevus cells are cytologically and biologically distinct from the melanocytes that colonize the basal cell layer of the epidermis and oral epithelium. Whereas native melanocytes tend to have a dendritic morphology, most nevic cells tend to be round, ovoid, or spindle shaped.20 Additional differences include the tendency for nevus cells to closely approximate one another, if not aggregate in clusters, and their ability to migrate into and/or within the submucosal tissues.
In general, both genetic and environmental factors are thought to play a role in nevogenesis. The effect of sun exposure on the development of cutaneous nevi is well recognized. However, there are also age‐ and location‐dependent differences in the presentation, number, and distribution of nevi. Although most melanocytic nevi are acquired, some may present as congenital lesions (including those in the oral cavity). Moreover, there are several examples of increased nevus susceptibility in various inherited diseases, thus confirming the role of genetics. To illustrate: familial atypical multiple mole and melanoma syndrome is characterized by the formation of histologically atypical nevi,21 blue nevus may be associated with the Carney complex,22 markedly increased numbers of common nevi are characteristic in patients with Turner’s syndrome23 and Noonan’s syndrome,24 and congenital nevi are typical of neurocutaneous melanosis.25 Thus, these findings also bring into question whether nevi are true benign neoplasms or hamartomatous or developmental in nature, as they have been historically characterized. A study by Pollock and colleagues demonstrated that up to 90% of dermal melanocytic nevi exhibit somatic, activating mutations in the BRAF oncogene.26 Mutations in the HRAS and NRAS oncogenes have also been identified.27,28 This lends further credence to the notion that cutaneous melanocytic nevi are neoplastic. It is currently unknown whether oral melanocytic nevi also harbor any of these same mutations.
Clinical Features
Cutaneous nevi are common. The average Caucasian adult may have several nevi; some individuals may have dozens. The total number of nevi occurring in males tends to be higher than that seen in females. In contrast, oral melanocytic nevi are rare solitary lesions that are more common in females.6
Oral melanocytic nevi have no distinguishing clinical characteristics. Lesions are usually asymptomatic and often present as a small (<1 cm), solitary, brown or blue, well‐circumscribed nodule or macule (Figure 5‐8). Up to 15% of oral nevi may be amelanotic. Once the lesion reaches a given size, its growth tends to cease and may remain static indefinitely. In rare cases, multifocal lesions have been described.29 Whereas some studies suggest a greater prevalence of oral nevi in black patients, other studies have not identified any significant racial predilection. Oral nevi may develop at any age; however, most are identified in patients over the age of 30. The hard palate represents the most common site, followed by the buccal and labial mucosae and gingiva.
Figure 5‐8 Intramucosal nevus of the right buccal mucosa.
Figure 5‐9 (A) Compound nevus: nevus cells are located at the junction of the epithelium and connective tissue and within the submucosal tissue. The cells are variably pigmented (hematoxylin‐eosin stain; ×400 original magnification). (B) Intramucosal nevus: the nevus cells are located within the lamina propria, with no evidence of any junctional component. The superficial melanocytes are heavily pigmented. Melanin is less evident in the remaining cells (hematoxylin‐eosin stain; ×100 original magnification).
Pathology
Nevus cells initially maintain their residency at the basal layer, as cellular clusters at the junction of the epithelium and the underlying connective tissue (Figure 5‐9). These junctional nevi are usually small (<5 mm), macular, and tan to brown in color. Over time, the clustered melanocytes are thought to proliferate down into the connective tissue, often in the form of variably sized nests of relatively small, rounded cells. Nonetheless, some nevus cells may still be seen at the epithelial–connective tissue interface. Such nevi often assume a dome‐shaped appearance and are referred to as compound nevi. As the lesion further matures, the nevus cells completely lose their association with the epithelial layer and become confined to the lamina propria, often with an associated decrease in the amount of pigmentation. At this point, the lesion is given the designation of intramucosal nevus and, clinically, may appear brown, tan, or may even resemble the color of the surrounding mucosa.
Blue nevi are characterized by a variety of microscopic features. The “common” blue nevus, which is the most frequent histologic variant seen in the oral cavity, is characterized by a stromal proliferation of pigment‐laden, spindle‐shaped melanocytes. The blue nevus is described as such because the melanocytes that reside deep in the connective tissue and the overlying fibrous connective tissue often conceal the brown color of melanin, resulting in a blue tint. The less frequently occurring cellular blue nevus is characterized by a stromal proliferation of both spindle‐shaped and larger round or ovoid‐shaped melanocytes. It should be noted that histologic differentiation of the two forms is not merely academic. Whereas the common blue nevus usually has an innocuous clinical course, the cellular blue nevus may behave more aggressively and exhibit a greater rate of recurrence.30 Rare reports of malignant transformation have also been associated with the cellular cutaneous variant.
While cutaneous acquired nevi and dysplastic nevi may represent precursors of malignant melanoma, there is no evidence of an increased malignant transformation rate for melanocytic nevi of the mouth. Nonetheless, it is advised that all oral nevi, regardless of histologic type, should be completely removed.31
Differential Diagnosis
The differential diagnosis includes a variety of other focally pigmented lesions, including malignant melanoma. Various vascular lesions and exogenous pigmentations may also be considered in the differential diagnosis.
Management
Biopsy is necessary for diagnostic confirmation of an oral melanocytic nevus. Complete but conservative surgical excision is the treatment of choice for oral lesions. Recurrence has only rarely been reported. Laser and intense pulse light therapies have been used successfully for the treatment of cutaneous nevi.32 However, their value in the treatment of oral nevi is unknown.
Malignant Melanoma
Etiology and Pathogenesis
Malignant melanoma is the least common but most deadly of all primary skin cancers. Similar to other malignancies, extrinsic and intrinsic factors play a role in its pathogenesis. A history of multiple episodes of acute sun exposure, especially at a young age; immunosuppression; the presence of multiple cutaneous nevi; and a family history of melanoma are all known risk factors for the development of cutaneous melanoma.33 Melanoma‐prone families have a high incidence of germline mutations in the tumor suppressor genes, CDKNA2/p16INK4a or, less commonly, CDK4.34 Similar to melanocytic nevi, melanomas also frequently exhibit mutations in the BRAF, HRAS, and NRAS proto‐oncogenes.27,35 Other recurrent molecular findings, including MC1R polymorphisms and alterations or loss of PTEN function, have also been described.36,37 This suggests that several distinct genetic changes are required for the molecular evolution of melanoma.
Clinical Features
Cutaneous melanoma is most common in white people living in sunbelt regions of the world. However, mortality rates are higher in black and Hispanic people. Epidemiologic studies suggest that its incidence is increasing in patients, especially males, over the age of 45.38 In contrast, the incidence is decreasing in patients under the age of 40. Despite an overall predilection for males, melanoma is one of the most commonly occurring cancers in women of child‐bearing age.39
Melanomas may develop either de novo or, less commonly, from an existing melanocytic nevus.33 The malar region is a common site for melanoma because this area is subject to significant solar exposure. In general, the clinical characteristics of cutaneous melanoma are best described by the ABCDE criteria: asymmetry, irregular borders, color variegation, diameter greater than 6 mm, and evolution or surface elevation. These criteria are very useful (although not absolute) in differentiating cutaneous melanoma from other focal, pigmented melanocytic lesions.40
There are four main clinicopathologic subtypes of cutaneous melanoma: superficial spreading melanoma, lentigo maligna melanoma, acral lentiginous melanoma, and nodular melanoma (Figures 5‐10 and 5‐11).33 In the first three subtypes, the initial growth is radial, where the melanocytic tumor cells spread laterally and therefore superficially. These lesions have a good prognosis if they are detected early and treated before the onset of nodular lesions, which would indicate invasion into the deeper connective tissue (i.e., a vertical growth phase). The development of nodularity in a previously macular lesion is an ominous sign.
The prognosis of melanoma can be ascertained by Breslow’s tumor thickness criteria, or Clark’s level of invasion. Microscopic findings such as surface ulceration, vascular or lymphatic invasion, neurotropism, high mitotic index, and absence of lymphocytes infiltrating the tumor are all associated with a poor prognosis.6 Additionally, various clinical parameters, including tumor site, age of the patient (>60 years), sex (male), and regional or distant metastasis, also are predictive of poor prognosis. The 5‐year survival rate of patients with metastatic melanoma is less than 15%.33
Figure 5‐10 Cutaneous macular melanoma fulfilling the ABCDE criteria.
Source: Courtesy of Dr. Gyorgi Paragh, Department of Dermatology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
Figure 5‐11 Ulcerated cutaneous nodular melanoma.
Source: Courtesy of Dr. Gyorgi Paragh, Department of Dermatology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
Awareness of the epidemiologic and biologic properties of cutaneous melanoma is necessary for the clinical practitioner. However, these factors have little bearing on the clinical, histologic, demographic, and biologic profiles associated with primary mucosal malignant melanoma. In brief, mucosal melanomas are very distinct neoplasms.41,42
Primary mucosal melanomas comprise less than 1% of all melanomas.41,43 The majority develop in the head and neck, mainly in the sinonasal tract and oral cavity. The prevalence of oral melanoma appears to be higher among black and Japanese people than in other populations.41,44 The tumor presents more frequently in males than in females. Unlike the cutaneous variant, which has distinct and well‐recognized risk factors associated with its development, the etiology of oral melanoma remains unknown. BRAF mutations are rarely observed in mucosal melanomas.42
Figure 5‐12 (A) Malignant melanoma exhibiting macular involvement of the anterior hard palate. Source: Courtesy of Dr. Guy DiTursi, VA Medical Center‐Buffalo, Buffalo, NY, USA. (B) Malignant melanoma presenting as a mass on the maxillary gingiva.
Courtesy of Dr. Rocio Fernandez, National Autonomous University of Mexico, Mexico City, Mexico.
Oral melanoma may develop at any age, but is most prevalent over the age of 50.44,45 Any mucosal site may be affected; however, the palate represents the most common site of involvement, followed by the maxillary gingiva/alveolar crest.46 Oral melanomas have no distinctive clinical features. They may present as macular, plaque like, or as a mass, well‐circumscribed or irregular, and may exhibit focal or diffuse areas of brown, blue, or black pigmentation (Figure 5‐12). Up to one‐third of oral melanomas exhibit little or no clinical evidence of pigmentation (amelanosis).47 In some cases, oral melanomas may display multifocal areas of pigmentation. This phenomenon most likely represents both melanotic and amelanotic areas.44,47
Additional signs and symptoms that may be associated with oral melanoma are nonspecific and similar to those observed with other malignancies. Ulceration, pain, tooth mobility or spontaneous exfoliation, root resorption, bone loss, and paresthesia/anesthesia may be evident. However, in some patients the tumors may be completely asymptomatic.43 Thus, the clinical differential diagnosis may be quite extensive and could include melanocytic nevus, oral melanotic macule, and amalgam tattoo, as well as various vascular lesions and other soft tissue neoplasms. It is for this reason that a biopsy of any persistent solitary pigmented lesion is always warranted.48
Oral mucosal malignant melanoma is associated with a very poor prognosis. Studies have demonstrated 5‐year survival rates of 15–40%.43,44 Involvement of the palate is predictive of the worst prognosis compared to other intraoral sites.49 Regional lymphatic metastases are frequently identified and contribute to the poor survival rate.50 Less than 10% of patients with distant metastases survive after 5 years.44 The 10‐year survival rate is 0%.51
Pathology
Microscopically, oral mucosal melanomas (like cutaneous melanomas) may exhibit radial or vertical growth patterns. The radial or superficial spreading pattern is often seen in macular lesions, where clusters of pleomorphic melanocytes exhibiting nuclear atypia and hyperchromatism proliferate within the basal cell region of the epithelium. Upward spreading of abnormal melanocytes (pagetoid spread) and superficial invasion of the papillary lamina propria are evident (Figure 5‐13).3 Once vertical growth into the connective tissue is established, the lesions become clinically tumefactive.
Owing to its rare occurrence, even the most renowned clinical cancer centers do not have a large enough cohort of oral melanoma cases to reliably and significantly correlate the histologic findings with prognosis.44 Thus, apart from tumor thickness greater than 5 mm and the presence of lymphovascular invasion, many of the histologic prognostic parameters of cutaneous melanoma (i.e., Breslow’s classification and Clark’s level of invasion) do not apply to oral melanoma.3,6,47
Figure 5‐13 Heavily pigmented malignant melanoma exhibiting a primarily radial growth phase with pagetoid spread of tumor cells (hematoxylin and eosin stain; ×400 original magnification).
Source: Photomicrograph courtesy of Dr. Julien Ghannoum.
Diagnosis
One of the main clinical and microscopic challenges in diagnosing oral melanoma is determining whether the lesion is a primary neoplasm or a metastasis from a distant site. This is not a semantic distinction, since confirming the primary site will dictate the patient’s clinical stage and the type of therapy they will undergo. A history of a previous melanoma, sparing of the palate and gingiva, amelanosis, and microscopic features such as a lack of junctional activity and pagetoid spread are findings that may be more suggestive of a metastatic tumor.6
Management
For primary oral melanomas, ablative surgery with wide margins remains the treatment of choice.3,44 Adjuvant radiation therapy may also be necessary.52 However, it remains unclear whether radiation therapy alone is beneficial for the treatment of oral mucosal melanoma.53 Computed tomography and magnetic resonance imaging studies should be undertaken to explore metastases to the regional lymph nodes. A variety of chemo‐ and immunotherapeutic strategies are often used if metastases are identified or for palliation.3
Melanoma is one of the most immunogenic cancers, and there are several clinical immunotherapeutic trials currently being conducted to test the effects of various antitumor vaccines. Adjuvant interferon‐α‐2B therapy has already been approved for the treatment of primary cutaneous melanomas more than 4 mm in thickness.54 Unusual side effects of chemo‐ and immunotherapy may include the onset of autoimmunity. The appearance of autoantibodies and clinical manifestations of autoimmune disease, including vitiligo, have been associated with statistically significant improvements in overall survival rates for patients with cutaneous melanoma.55 The discovery of KIT and BRAF mutations and the development of novel immunotherapeutic agents that specifically target and inhibit these oncogenic pathways have provided new alternative treatments.56 Small molecule targeted therapy (BRAF and MEK inhibitors) and immune checkpoint inhibitors (CTLA‐4 and PD‐1) have shown promising clinical outcomes. However, the adverse effects associated with BRAF and MEK inhibitors are extensive, ranging from inflammatory to malignant conditions. Similarly, immune checkpoint inhibitors may result in a number of adverse side effects including autoimmunity (e.g., bullous pemphigoid, lichen planus pemphigoid, dermatomyositis, etc.). Viral oncolytic therapies (using a modified herpes simplex virus‐1) are now also available. Collectively, these novel therapeutic venues for the treatment of melanoma have improved overall survival.57
MULTIFOCAL/DIFFUSE PIGMENTATION
Physiologic Pigmentation
Physiologic pigmentation is the most common multifocal or diffuse oral mucosal pigmentation (Table 5‐4). Dark‐complexioned individuals, including black, Asian, and Latino people, frequently show patchy to generalized hyperpigmentation of the oral mucosal tissues. In many patients, the pigment is restricted to the gingiva; however, melanosis of other mucosal surfaces is not uncommon (Figure 5‐14). The pigment is typically first observed during childhood and does not develop de novo in the adult. The sudden or gradual onset of diffuse mucosal pigmentation in adulthood, even in darker‐skinned patients, should alert the clinician to contemplate a pathologic genesis. A wide differential diagnosis should be considered (i.e., drug‐induced or smoking‐induced melanosis, an endocrinopathy, or a syndromic condition). A thorough history and laboratory tests are necessary to obtain a precise diagnosis.
Microscopically, physiologic pigmentation is characterized by the presence of increased amounts of melanin within the basal cell layer. This pigmentation is considered a variation of normal. Nonetheless, the appearance of brown to black discoloration, even intraorally, can be esthetically displeasing to some patients. Thus, surgical intervention may be necessary. Gingivectomy, laser therapy, and cryosurgery can all effectively remove oral pigmentation.58 However, with each of these modalities, there is a possibility that the pigmentation may eventually recur. The mechanism of such repigmentation remains unclear.
Table 5‐4 Etiology of multifocal, diffuse, or generalized mucocutaneous melanosis.
| Physiologic pigmentation |
| Laugier–Hunziker pigmentation |
| Postinflammatory hyperpigmentation |
| Drug‐induced |
| Hormone‐induced |
| Adrenal insufficiency |
| Cushing’s syndrome/Cushing’s disease |
| Hyperthyroidism |
| Primary biliary cirrhosis |
| Hemochromatosis (early stages) |
| Genetic disease |
| Vitamin B12 deficiency |
| HIV/AIDS (late stages) |
| Malignant melanoma |
Figure 5‐14 Physiologic pigmentation of the maxillary and mandibular gingiva. Note the patchy distribution of the pigment.
Source: Courtesy of Dr. Christine Chu, private practice, New York, USA.
Drug‐Induced Melanosis
Etiology and Pathogenesis
Medications may induce a variety of different forms of mucocutaneous pigmentation, including melanosis. Pigmentation that is caused by the soft tissue deposition of drug metabolites or complexes and pigment associated with deposition of lipofuscin or iron are discussed later in this chapter.
The chief drugs implicated in drug‐induced melanosis are the antimalarials, including chloroquine, hydroxychloroquine, and quinacrine (Figure 5‐15).59
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