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 prac-
tice. 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 attrib-
uted to a local phenomenon and/or associated
with an underlying systemic disorder. Diag-
nostic and therapeutic modalities must be care-
fully considered as these lesions encompass the
spectrum of clinical pathology, ranging from
benign to malignant. Clinicians should conduct
a thorough medical history and relevant phys-
ical examination for patients with pigmented
lesions to identify possible adrenal, gastroin-
testinal, 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
e-mail: ets@upenn.edu
F. Alawi
Department of Pathology, University of Pennsylvania
School of Dental Medicine, Philadelphia, PA, USA
e-mail: falawi@upenn.edu
# Springer International Publishing AG 2017
C.S. Farah et al. (eds.), Contemporary Oral Medicine,
DOI 10.1007/978-3-319-28100-1_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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Melanocytic Nevus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Malignant Melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Multifocal/Diffuse Pigmentation . . . . . . . . . . . . . . . . . . . . 14
Physiologic Pigmentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Drug-Induced Melanosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Smoker’s Melanosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Post-inflammatory (Inflammatory)
Hyperpigmentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Laugier-Hunziker Pigmentation . . . . . . . . . . . . . . . . . . . . . . 18
Pigmentation Associated with Systemic or Genetic
Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Adrenal Insufficiency (Addison Disease) . . . . . . . . . . . . . 19
Cushing Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Human Immunodeficiency Virus (HIV): Associated
Pigmentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Peutz-Jeghers Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
Exogenous Causes of Clinical Pigmentation . . . . . . . 26
Tattoos: Amalgam, Graphite, and Ornamental . . . . . . . 26
Metal-induced Discoloration . . . . . . . . . . . . . . . . . . . . . . . . . . 28
1
2 E.T. Stoopler and F. Alawi

Conclusion and Future Directions . . . . . . . . . . . . . . . . . . 28 systemic or genetic disorders, and exogenous

Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 causes of clinical pigmentation (Table 1).
Melanocytes are derived from neural crest cells
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
and are located in the basal epithelial layer
of squamous mucous membranes (Meleti et al.
2008). The functions of melanocytes are not
Introduction
fully understood, but the melanin produced
by these cells absorb ultraviolet light, scavenge
The mucous membranes lining the oral cavity are
reactive oxygen species, and determine skin, hair,
not uniformly colored and dependent upon the spe-
and eye color (Meleti et al. 2008; Feller et al.
cific anatomic location; healthy tissue commonly
2014a, b). Oral melanocytes are regularly inter-
ranges in color from white to red-purple. This is due
spersed between basal keratinocytes, and melanin
to the interaction of various tissues that compose the
from the melanocytes are transported and trans-
mucosal lining, including presence or absence of
mitted to epithelial cells via dendritic migration of
keratin on the surface epithelium, location and pres-
melanosomes (melanin-containing vesicles). The
ence of vascular structures in the stroma, existence
ratio of melanocytes to keratinocytes in the basal
of adipocytes, and the lack of melanin pigmentation
epithelial layer ranges from 1:10 to 1:15 (Feller
in the basal cell layer of the epithelium. Pigment
et al. 2014a, b). Two chemically distinct types of
deposition, whether physiologic or pathologic, or
melanin exist, eumelanin (brown-black) and
attributed to endogenous or exogenous substances,
pheomelanin (red/yellow), and melanogenesis is
will impart gray, blue, brown and/or black color
considered a mixed process between these mela-
changes to the oral mucosa. The most common
nin types, with proportions of eumelanin and
endogenous sources of pigmentation are melanin,
pheomelanin being genetically determined (Feller
hemoglobin, and hemosiderin, while exogenous
et al. 2014a, b). There are no numerical or struc-
sources of pigmentation are usually attributed to
tural differences in oral melanocytes between
traumatic or iatrogenic events that result in deposi-
tion of foreign material directly into the mucosal Table 1 Pigmented lesions of the oral mucosa
tissues. Several parameters associated with
I. Focal pigmentation conditions
pigmented lesions, such as location, shape, color,
a. Freckle/ephelis
and size, must be assessed in order for clinicians to b. Oral/labial melanotic macule
appropriately evaluate and manage the condition, as c. Oral melanoacanthoma
pathology of pigmented lesions ranges from benign d. Melanocytic nevus
to malignant. Clinicians should conduct a thorough e. Malignant melanoma
medical, family, and social history, as well as a II. Multifocal/diffuse pigmentation conditions
relevant physical examination for patients with a. Physiologic pigmentation
pigmented lesions, to identify possible adrenal, gas- b. Drug-induced melanosis
trointestinal, or genetic disorders that are commonly c. Smoker’s melanosis
associated with these types of lesions. If a systemic d. Post-inflammatory (inflammatory) hyperpigmentation
disorder is suspected, the patient should be e. Laugier-Hunziker pigmentation
promptly referred to the appropriate health-care III. Pigmentation associated with systemic or genetic
disorders
provider for further evaluation and management.
a. Adrenal insufficiency (Addison disease)
Multidisciplinary care is often necessary to effec-
b. Cushing disease
tively manage patients with these conditions. This
c. Human immunodeficiency virus (HIV) – associated
chapter provides a contemporary perspective of pigmentation
pigmented lesions of the oral mucosa focusing on d. Peutz-Jeghers syndrome
those associated with melanin and will discuss focal IV. Exogenous causes of clinical pigmentation
pigmentation conditions, multifocal or diffuse pig- a. Tattoos – amalgam, graphite and ornamental
mentation conditions, pigmentation associated with b. Metal – induced discoloration
Pigmented Lesions of the Oral Mucosa
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 dis-
tribution 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 predilec-
tion, 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 poly-
morphisms 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 produc-
tion without an increase in the number of melano-
cytes 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 brown-
colored, 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
3
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 vari-
ability 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). Sun-
screens 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 spo-
radic 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 repre-
sent a reactive or a physiologic process (Meleti
et al. 2008).
4 E.T. Stoopler and F. Alawi
Fig. 1 Freckle (ephelis) [arrow] on the facial skin
Fig. 2 Biopsy-proven gingival melanotic macule
appearing as brown pigmented lesion involving the inter-
dental gingiva between 41 and 42 (Photo courtesy: Profes-
sor Camile Farah, Perth Oral Medicine & Dental Sleep
Centre, Perth, WA, Australia)
Pathophysiology
Oral/labial melanotic macules are caused by an
increased production and deposition of melanin
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, well-
circumscribed 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. 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. 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
Pigmented Lesions of the Oral Mucosa
Fig. 5 Biopsy-proven melanotic macule involving the
hard palate demonstrating irregular pigmentation and bor-
der viewed with white light (a) and with optical fluores-
cence imaging VELscope Vx (b) showing loss of
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 mel-
anin in the basal and parabasal layers of normal
stratified squamous epithelium without an
5
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 typi-
cally demonstrate elongated rete ridges (Alawi
2013).
Patient Management
Oral/labial melanotic macules are considered
benign lesions without malignant potential
(Kauzman et al. 2004). Since early malignant
melanoma may have a similar clinical appearance
and exhibits a predilection for the maxillary alve-
olar mucosa and palate, it is strongly advisable to
perform an excisional biopsy for any suspected
oral/labial melanotic macule for histopathologic
analysis (Kauzman et al. 2004). Labial melanotic
macules may be of cosmetic concern, and removal
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 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 His-
panic, 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 pig-
mentation that may range in size from a few
millimeters to several centimeters (Alawi 2013;
Arava-Parastatidis et al. 2011) (Fig. 7). The lesion
is typically brown to black in color with possible
heterogeneity of color throughout the lesion.
Oral melanoacanthoma usually manifests as a
solitary lesion, but multifocal lesions have been
reported (Arava-Parastatidis et al. 2011). Oral
melanoacanthoma is most frequently observed
on the buccal mucosa followed by the palate,
lips, gingiva, and tongue and may present unilat-
erally or bilaterally (Alawi 2013; Arava-
Parastatidis et al. 2011). This condition is primar-
ily asymptomatic; however, some patients report
burning sensations and/or pruritus associated with
these lesions (Cantudo-Sanagustín et al. 2016).
Histologically, oral melanoacanthoma is charac-
terized by spongiotic epithelium containing den-
dritic pigmented melanocytes throughout the
lesional epithelium (Alawi 2013) (Fig. 8). A
mild to moderate inflammatory infiltrate com-
posed of lymphocytes and occasional eosinophils
is observed in the underlying connective tissue
(Alawi 2013).
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
Pigmented Lesions of the Oral Mucosa
develop due to melanocytic growth and prolifera-
tion (Alawi 2013; Hatch 2005). Cutaneous nevi
are common and typically develop during child-
hood 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 proto-
oncogenes (Alawi 2013; Meleti et al. 2008). It
remains unclear if similar mutations are impli-
cated 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 differenti-
ating clinical and histologic features (Alawi
2013). Melanocytic proliferation can be consid-
ered in three phases that correspond to each of the
aforementioned nevi types: (1) proliferation of
benign neoplastic melanocytes along the
epithelial-mesenchymal junction (i.e., junctional
7
nevus), (2) migration of these cells into the mes-
enchymal 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 charac-
teristic 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 E.T. Stoopler and F. Alawi
Fig. 10 Blue nevus (arrow) identified on the palate
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, respec-
tively (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
Fig. 12 Intramucosal nevus composed of heavily
pigmented nevus cells (hematoxylin and eosin, 200)
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 pigment-
laden, spindle-shaped melanocytes (Fig. 13),
while the cellular blue nevus demonstrates sub-
mucosal 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 neces-
sary to confirm the diagnosis of oral melanocytic
nevi as the clinical presentation resembles other
focally pigmented lesions, such as malignant mel-
anoma (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
Pigmented Lesions of the Oral Mucosa
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 approx-
imately four- to fivefold (Lim et al. 2014). Over-
all, 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 malig-
nant 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 mela-
noma is lower compared to nonmelanoma skin
cancers, it accounts for the vast majority of skin
cancer deaths (Lee et al. 2017). Malignant mela-
noma is most common among white populations
residing in Sunbelt regions of the world (Berwick
et al. 2016). International incidence of melanoma
9
varies depending on geographic regions with the
highest rates of malignant melanoma occurring in
New Zealand, Australia, and the United States
(Jiang et al. 2015). It is estimated that 1 in 50 per-
sons in the United States will be diagnosed with
malignant melanoma during his or her lifetime
(Lim et al. 2014). It accounts for approximately
4.6% of all new cancers and 1.7% of all cancer-
related deaths in the United States (Gandhi and
Kampp 2015). Incidence of malignant melanoma
in European countries varies widely with approx-
imately 2 to 20 cases diagnosed per 100,000
annually (Jiang et al. 2015). Malignant melanoma
incidence in Asia, Africa, and Central and South
America is considered low; however, the overall
international incidence trends of malignant mela-
noma suggest it is continuing to increase (Jiang
et al. 2015). Median age of diagnosis is 64 years;
however, incidence of malignant melanoma
increases with age, reaching a peak between
80 and 84 years (Gandhi and Kampp 2015). Over-
all, there is a male predilection for the condition,
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 dis-
ease 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 com-
prises 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 mel-
anoma 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
et al. 2008). Unlike cutaneous malignant mela-
noma, histopathologic parameters cannot be reli-
ably used to determine prognosis of oral
malignant melanoma (Alawi 2013). Oral malig-
nant 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 mel-
anoma, with ultraviolet radiation, primarily ultra-
violet 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 ultravio-
let light are tanning beds, and several recent stud-
ies 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 high-
penetrance susceptibility genes, the cyclin-
dependent 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 susceptibil-
ity gene, and alterations of the BRAF, HRAS, and
NRAS proto-oncogenes, and alteration or loss of
PTEN function, have been associated with malig-
nant 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
E.T. Stoopler and F. Alawi
fivefold (Lim et al. 2014). Sun protection at
an early age may lower the subsequent risk of
malignant melanoma (Lim et al. 2014; MacLen-
nan 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 clini-
cal appearances, with early lesions typically char-
acterized by a macule or plaque with different
hues (brown, black, blue, red, or white) or occa-
sionally 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 ele-
vation) 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 distribu-
tion 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
Pigmented Lesions of the Oral Mucosa
Fig. 14 Superficial spreading melanoma of the scalp
(1.2 mm in depth) in an 86-year-old male (Photo courtesy:
Dr. Simon Lee, Head of Surgery, The Skin Hospital, Fig. 16 Nodular melanoma on the toe (5.7 mm in depth)
Darlinghurst, NSW, Australia)
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,
11
in a 67-year-old male (Photo courtesy: Dr. Simon Lee,
Head of Surgery, The Skin Hospital, Darlinghurst, NSW,
Australia)
a superficial spreading melanoma appears varie-
gated with a sharply marginated, irregular border
and is typically smaller than 3 cm (Lim et al.
2014). Multiple hues and shades are often noted
with superficial spreading melanoma, such as tan,
brown, gray, black, blue, white, and pink (Lim
et al. 2014) (Figs. 14 and 15). Nodular melanoma
represents 15% of cutaneous melanomas and is
more common in men (Lim et al. 2014). Typically,
they are found on the trunk, and, interestingly,
one-third of lesions develop in the head and neck
(Lim et al. 2014). Clinically, nodular melanoma
may be deeply pigmented (Fig. 16); however, due
to the possibility of melanoma cells being so
poorly differentiated, these cells may stop produc-
ing melanin, resulting in a nonpigmented
amelanotic macule. 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 pre-
sents 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 E.T. Stoopler and F. Alawi

along the basal layer of the surface epithelium

prior to invasion of the underlying connective
tissue, which is described as radial extension
(Lim et al. 2014). Pagetoid and nested epithelioid
melanocytes cells in the intraepidermal portion
with poor circumscription are characteristic of
superficial spreading melanoma (Lim et al.
2014). In contrast, nodular melanoma is charac-
terized by vertical growth of malignant melano-
cytes into the connective tissue, which typically
occurs early in the disease process. The tumor
usually appears as pleomorphic, spindle-shaped,
Fig. 17 Malignant melanoma present on the lower labial
mucosa or epithelioid cells arranged in loosely aggregated
sheets and cords.
Oral malignant melanomas are usually charac-
mucous membranes and presents as a variably
terized by sheets or islands of malignant melano-
colored macule, usually brown or black, which
cytes within the connective tissue with possible
develops irregular borders and increases in size
pagetoid spread (Alawi 2013; Chatzistefanou
over time (Lim et al. 2014).
et al. 2016) (Fig. 19). Poorly differentiated tumors
Oral malignant melanoma, however, has no
may exhibit only minimal pigment or none at all
such distinctive clinical appearance and is often
(Fig. 20). Like its cutaneous counterpart, oral
initially asymptomatic. The lesion typically
malignant melanomas exhibit an initial radial
begins as a brown to black macule with irregular
growth phase, typically followed by a vertical
borders and may even lack pigment (Hashemi
pattern of growth with deeper tissue invasion
Pour 2008) (Fig. 17). Lesions are relatively soft
(Chatzistefanou et al. 2016). The presence of
to palpation and may be accompanied by ery-
malignant cells in the lamina propria and a high
thema and/or ulceration, which can potentially
tumor mitotic rate are characteristic of invading
cause pain (Mohan et al. 2013). Tooth mobility
activity (Chatzistefanou et al. 2016). Immunohis-
or spontaneous exfoliation, root resorption, anes-
tochemistry studies using antibodies directed
thesia/paresthesia, and bone loss may be evident
against HMB45, S100, MART1, and/or micro-
(Mohan et al. 2013). Diffuse, contiguous muco-
phthalmia-associated transcription factor (MitF)
sal pigmentation should be viewed suspiciously
are necessary for definitive diagnosis of oral
as possible malignant melanoma compared to
malignant melanoma (Muller 2010) (Fig. 21).
diffuse, noncontiguous pigmentation (Alawi
2013). While any mucosal site may be affected,
the palate is the most common intraoral location
Patient Management
Biopsy is mandatory for any persistent solitary
of oral malignant melanoma followed by the
pigmented lesion, as they can be representative
maxillary gingiva/alveolar crest (Femiano et al.
of a variety of processes, from innocuous lesions
2008) (Fig. 18a, b). There may be radiographic
to life-threatening malignant melanoma (Mohan
evidence of “moth-eaten” or irregular bone
et al. 2013). Once malignant melanoma is diag-
destruction associated with these lesions, and
nosed, it is important, yet challenging, to deter-
cervical lymph nodes may be palpable due to
mine if the lesion represents a primary malignancy
metastasis at initial presentation (Hashemi Pour
or a metastasis from a distant site, as this informa-
2008).
tion will dictate tumor staging and direct therapy
Microscopically, superficial spreading mela-
(Alawi 2013). Surgical excision is the primary
noma, lentigo maligna melanoma, and acral
treatment modality for malignant melanoma,
lentiginous melanoma demonstrate a lateral and
which is curative for most patients with early-
superficial spread of melanocytic tumor cells
Pigmented Lesions of the Oral Mucosa
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 ante-
rior teeth (a). Hematoxylin- and eosin-stained histological
section of lesion demonstrating brown pigment in
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 dissec-
tion is typically performed on patients with clini-
cally 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 mel-
anoma, 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 mono-
clonal 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 resis-
tant compared with other cancers (Lim et al.
2014).
13
malignant cells and superficial underlying connective tis-
sue (b) (Photo courtesy: Professor Camile Farah, Oral
Health Centre of Western Australia, School of Dentistry,
University of Western Australia, Perth, WA, Australia)
Multifocal/Diffuse Pigmentation
Physiologic Pigmentation
Epidemiology
Physiologic (“racial”) pigmentation is the most
common multifocal or diffuse oral mucosal pig-
mentation; 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 pre-
dilection (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
Fig. 19 Mucosal melanoma. Sheets and cords of malig-
nant melanocytes scattered throughout the lamina propria
(hematoxylin and eosin, 100)
Fig. 20 Amelanotic melanoma exhibiting only focal pig-
mentation (arrow). The tumor cells are poorly differenti-
ated (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
E.T. Stoopler and F. Alawi
Fig. 21 Anti-HMB45 immunohistochemical analysis.
The malignant tumor cells (see Fig. 6) were strongly reac-
tive with the melanocytic marker HMB45
intensity of the lesions may be influenced by
hormones, smoking, and systemic medications
(Muller 2010).
Clinical-Pathologic Features
Physiologic pigmentation typically affects the
gingiva, where it presents as a bilateral, well-
demarcated, ribbon-like band of brown pigment
that usually does not affect the marginal gingiva
nor interfere with normal tissue architecture
(Kauzman et al. 2004; Tarakji et al. 2014)
(Figs. 22 and 23). Other sites that may be affected
include the buccal mucosa, lips, palate, and
tongue (Kauzman et al. 2004). The color associ-
ated with this condition ranges from light brown
to black, and patients affected by physiologic
pigmentation are asymptomatic (Muller 2010;
Tarakji et al. 2014). Microscopically, this condi-
tion is characterized by the presence of increased
amounts of melanin deposition within the basal
cell layer (Gondak et al. 2012) (Fig. 24).
Patient Management
Diagnosis of physiologic pigmentation is typi-
cally 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
Pigmented Lesions of the Oral Mucosa
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 pig-
mentation along the attached gingiva (Photo courtesy: Pro-
fessor 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 even-
tually recur. The practice of gingival tattooing in
females is a custom that is practiced among sev-
eral African ethnic groups and may appear clini-
cally similar to physiologic pigmentation (Rawal
et al. 2007). Traditionally, products such as lan-
tern 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. 2007.) 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).
15
Fig. 24 Physiologic pigmentation. Anti-MART1 anti-
body 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; chemothera-
peutic agents including bleomycin, busulfan, fluo-
rouracil, 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 E.T. Stoopler and F. Alawi

Fig. 25 Extensive gray/black coloration of the maxillary

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

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

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

Post-inflammatory (Inflammatory)
Hyperpigmentation

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

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

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

Patient Management
Fig. 29 Post-inflammatory pigmentation on the left buc-
Treatment is directed toward managing the under- cal mucosa in a patient with mild oral lichen planus (Photo
lying inflammatory condition when symptomatic, courtesy: Professor Camile Farah, Perth Oral Medicine &
typically with topical corticosteroids. Pigmenta- Dental Sleep Centre, Perth, WA, Australia)
tion may or may not resolve with resolution of the
lichenoid inflammation, and if it does, it may take
several months to fade (Alawi 2013).
Pigmented Lesions of the Oral Mucosa
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; Yago et al. 2008). This condi-
tion 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 pigmen-
tation 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 mel-
anin 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 involve-
ment with fingernails more commonly affected
than toenails (Fernandes et al. 2015). Similar
lesions may be observed on other cutaneous
19
surfaces, such as the facial skin and abdomen,
and other mucosal surfaces, including the esoph-
agus, conjunctiva, and anogenital mucosa (Alawi
2013; Nikitakis and Koumaki 2013). Typical his-
tologic findings associated with Laugier-Hunziker
pigmentation include increased basal keratinocyte
melanin without an increase in number of mela-
nocytes, melanin incontinence, and epithelial
acanthosis in the absence of rete ridges or inflam-
mation (Nikitakis and Koumaki 2013).
Patient Management
Treatment for this condition is typically not indi-
cated unless there is an esthetic and/or psycholog-
ical 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 con-
ditions 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 neces-
sary. 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; Yago et al. 2008).
Pigmentation Associated
with Systemic or Genetic Disorders
Adrenal Insufficiency (Addison
Disease)
Epidemiology
Adrenal insufficiency is a potentially life-
threatening endocrinopathy that is characterized
by diminished production of glucocorticoids
20
(cortisol) with or without a concomitant defi-
ciency in mineralocorticoid and adrenal androgen
levels (Naziat and Grossman 2000). Dysfunction
in the hypothalamus-pituitary-adrenal gland axis
gives rise to adrenal insufficiency. Primary, sec-
ondary, and tertiary forms of adrenal insufficiency
are dependent upon the anatomic site of origin
precipitating the dysfunction.
An estimated 4.4–6 new cases of primary adre-
nal insufficiency develop per million people per
year (Charmandari et al. 2014). In contrast, sec-
ondary adrenal insufficiency is more common
than the primary disease with an estimated preva-
lence of 150–280 per million people. Overall, the
prevalence of Addison disease in Caucasians is
estimated to be between 1 in 8000–20,000 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) associ-
ated 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 hor-
mones act synergistically on the pituitary gland
to activate pro-opiomelanocortin (POMC) gene
expression (Anderson et al. 2016). The
corresponding 241 amino acid POMC polypep-
tide then undergoes an array of posttranslational
modifications to yield several biologically distinct
hormone peptides. These include adrenocortico-
tropic hormone (ACTH); α-, β-, and
γ-melanotropins (also known as melanocyte stim-
ulating 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 adre-
nal cortex to stimulate glucocorticoid production
and release. Once serum cortisol levels are stabi-
lized, ACTH and CRH synthesis are inhibited
E.T. Stoopler and F. Alawi
through an intricate negative feedback mecha-
nism. When reduced cortisol levels are sensed
by the hypothalamus, the CRH-POMC-ACTH-
cortisol signaling cascade is reactivated.
OMH is observed only in primary adrenal
insufficiency (Charmandari et al. 2014). The con-
stitutively 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 cas-
cade 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 post-
translational cleavage (Anderson et al. 2016).
Since α-MSH is a potent stimulator of melano-
genesis, this triggers the mucocutaneous pigmen-
tation 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 adre-
nocortical 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 disor-
ders may lead to congenital defects in adrenal
gland structure and function. Other genetic dis-
eases may affect sensitivity of the glands to
ACTH, limit glucocorticoid synthesis, or acceler-
ate 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 insuf-
ficiency and other endocrinopathies, including
Pigmented Lesions of the Oral Mucosa
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)
hypothyroidism and alterations of glucose metab-
olism (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 insuf-
ficiency 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 hyper-
pigmentation is not clinically significant, its sud-
den appearance may necessitate evaluation of the
patient for Addison disease.
21
Patient Management
Treatment of adrenal insufficiency should be
implemented as soon as a deficiency state is rec-
ognized. Glucocorticoid replacement therapy via
oral hydrocortisone supplementation (15–25 mg
daily divided in two or three doses) is usually the
treatment of choice (Napier and Pearce 2014). The
exact daily dosage should be titrated based on the
patient’s weight; higher dosing is typically
recommended for heavier patients. Low-dose
oral prednisone therapy (3–5 mg once daily) or
intramuscular dexamethasone (0.5 mg once daily)
can also be used. Dexamethasone injections are
recommended for patients who are unable to tol-
erate oral medications. Mineralocorticoid- and
androgen-replacement therapy is also frequently
necessary. Once serum cortisol levels normalize,
the pigmentation may eventually resolve.
Cushing Disease
Cushing syndrome is a potentially life-
threatening disease caused by prolonged exposure
to hypercortisolism that may arise from exoge-
nous 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 syn-
drome 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 syn-
drome (Sharma et al. 2015). Cushing disease is
primarily induced by an ACTH-secreting pitui-
tary adenoma. Other ACTH-dependent forms of
Cushing syndrome may arise from ectopic
ACTH- or, rarely, CRH-secreting tumors origi-
nating in other anatomic sites. ACTH-
independent Cushing syndrome develops sec-
ondary to functional adrenal neoplasms (Lacroix
et al. 2015). Oral melanocytic pigmentation only
develops in ACTH-dependent Cushing syn-
drome. The ensuing discussion will focus on
Cushing disease.
22
Epidemiology
The estimated incidence rate of endogenous
Cushing syndrome is 0.7–2.4 per million
populations per year, with a standardized mortal-
ity ratio of almost four (Sharma et al. 2015). It is
possible that incidence rates of endogenous Cush-
ing syndrome are underestimated. Studies of
patients with uncontrolled diabetes, hypertension,
or early-onset osteoporosis have revealed previ-
ously 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 appropri-
ate treatment, the risk for disease-related morbid-
ity 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 com-
plications 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 preva-
lence of 39.1 per million persons. Overall, females
are more commonly afflicted than males; ratios of
3–5:1 have been reported. Although Cushing dis-
ease can present at any age, most cases are diag-
nosed 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 precipi-
tate ACTH-dependent ectopic Cushing syn-
drome. These include small cell neuroendocrine
and carcinoid tumors of the lung and other
organs, islet-cell tumors of the pancreas, medul-
lary thyroid carcinoma, pheochromocytomas,
and thymomas. Hyperpigmentation may be
observed in any ACTH-dependent form of Cush-
ing syndrome.
E.T. Stoopler and F. Alawi
Pathophysiology
Excessive and pathologically constitutive secre-
tion 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 muco-
cutaneous pigmentation develops via the same
mechanism as that described for primary adrenal
insufficiency, i.e., α-MSH levels increase in par-
allel 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 muta-
tions of the MEN1 and CDKN1B genes precipi-
tate MEN1 and MEN4 syndromes, respectively
(Schernthaner-Reiter et al. 2016).
Germline mutations in the aryl-hydrocarbon
receptor-interacting protein predispose to pitui-
tary 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 sub-
unit [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. Caf-
é-au-lait pigmentation does not occur within the
oral cavity.
Clinical-Pathologic Features
Oral mucosal and/or cutaneous hyper-
pigmentation may be one of the earliest signs of
Cushing disease (Lacroix et al. 2015) (Fig. 31).
More significantly, prolonged exposure to hyper-
cortisolism 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, hyper-
tension, amenorrhea, osteoporosis, hirsutism,
abdominal striae, dorsocervical fat pads (“buffalo
Pigmented Lesions of the Oral Mucosa
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 sup-
pression, male impotence, and female infertility
(Lacroix et al. 2015).
Patient Management
There is no specific treatment for the pigmenta-
tion. Treatment of the underlying cause of Cush-
ing 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 inopera-
ble, 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. Pitui-
tary targeting is designed to inhibit ACTH syn-
thesis 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 can-
didates or who failed surgical therapy (Lau et al.
2015). Steroidogenic inhibitors including ketoco-
nazole may be used to inhibit cortisol synthesis.
Mifepristone is a progesterone receptor antagonist
that also inhibits glucocorticoid receptor activity.
Mifepristone reduces the hyperglycemia associ-
ated with Cushing disease. Resolution of the bio-
chemical defect will result in normalization of
ACTH and α-MSH levels. Over time, the pigmen-
tation may eventually resolve.
23
Human Immunodeficiency Virus (HIV):
Associated Pigmentation
Epidemiology
OMH is a recognized occurrence in HIV-seropos-
itive and AIDS-afflicted individuals. If it
develops, the pigmentation usually becomes
apparent within the first 2 years after initial HIV
diagnosis and usually in patients with CD4+ T-cell
counts of 200 cells/mm3 or less (Feller et al.
2014a). A potential relationship between viral
load and OMH remains uncertain.
The overall prevalence of OMH is not known.
However, there are geographic and ethnic differ-
ences 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, 18.5–38%
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%, respec-
tively, of all examined patients. In general, muco-
sal 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 pigmenta-
tion is multifactorial. There is currently no evi-
dence 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
More commonly, OMH may arise in response
to treatment with a number of different medica-
tions frequently used to treat HIV/AIDS and its
associated complications; zidovudine (azidothy-
midine [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 antire-
troviral therapy (ART) than in ART-naïve
individuals.
Primary or secondary adrenocortical dysfunc-
tion 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 pig-
mentation (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 mela-
nin incontinence within the papillary lamina pro-
pria (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 dis-
crete 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 darker-
skinned individuals, differentiating
HIV-associated pigment from physiologic
E.T. Stoopler and F. Alawi
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 pos-
sible infection.
Peutz-Jeghers Syndrome
Peutz-Jeghers syndrome (PJS) is an autosomal
dominant disorder associated with oral and peri-
oral melanocytic pigmentation, benign
hamartomatous polyps of the gastrointestinal
tract, and increased risk for developing malignan-
cies of the gastrointestinal tract, breast, uterine
cervix, ovary, pancreas, and other anatomic sites
(Riegert-Johnson et al. 2009). The risk is esti-
mated to be 18-fold higher than that of the general
population. The hyperpigmentation often mani-
fests 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. Nonethe-
less, PJS has an estimated incidence of 1 in
8000–200,000 live births without gender or racial
predilection (Riegert-Johnson et al. 2009). Mor-
tality 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
Pigmented Lesions of the Oral Mucosa
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 cel-
lular 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 mucocutane-
ous 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 hyper-
pigmentation remain unclear.
Clinical-Pathologic Features
PJS is commonly associated with multiple mela-
notic macules of the lips accompanied by diffuse
25
freckling of the perioral skin (Ponti et al. 2016)
(Fig. 32). The pigmented macules may coalesce to
produce broader areas of pigmentation. Less com-
monly, intraoral pigmentation may also be
observed; the tongue and buccal and/or labial
mucosae are typically affected. Pigmented spots
are also commonly observed on the fingertips.
The pigmentation typically presents during
infancy, childhood, or adolescence, and is often
the first sign of PJS. At least some of the pigmen-
tation may spontaneously resolve with age.
A biopsy of a pigmented lesion usually reveals
nonspecific histopathology (Ponti et al. 2016).
There is increased melanin pigmentation within
the basal epithelial layer and melanin inconti-
nence within the papillary lamina propria. There
may also be evidence of melanocytic hyperplasia.
Note that while highly characteristic, the pat-
tern of labial and perioral pigmentation is not
pathognomonic for PJS. Laugier-Hunziker pig-
mentation 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 pig-
mentation typically manifests during adulthood
and may be accompanied by pigmentation of the
nails. Patients with Laugier-Hunziker pigmenta-
tion do not exhibit STK11 mutations, and they do
not manifest with gastrointestinal polyps.
Apart from the gastrointestinal polyps and can-
cer, 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 pigmenta-
tion 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 clini-
cal 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
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 endoge-
nous 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 usu-
ally 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.
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
E.T. Stoopler and F. Alawi
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 embed-
ded within the lamina propria and/or submu-
cosa. Similarly, graphite tattoos may appear
clinically identical to amalgam tattoos
(Fig. 37). Graphite tattoos are caused by the
mucosal implantation of graphite particles typ-
ically 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 previ-
ously in this chapter (Gondak et al. 2012). The
tattoo ink is usually plant based and may be com-
bined 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).
(c) views confirming presence of amalgam particles (Photo
courtesy: Professor Camile Farah, Perth Oral Medicine &
Dental Sleep Centre, Perth, WA, Australia)
Pigmented Lesions of the Oral Mucosa
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. 35 Biopsy-proven amalgam tattoo appearing clini-
cally as black pigmented lesion in a 30-year-old female at
the mucogingival junction adjacent to virgin canine and
premolar teeth with braces. Lesion was remnant from
heavily restored primary dentition (Photo courtesy: Profes-
sor Camile Farah, Perth Oral Medicine & Dental Sleep
Centre, Perth, WA, Australia)
27
Fig. 36 Amalgam tattoo appearing clinically as black
pigmented lesion in a 65-year-old female presenting on
the buccal mucosa adjacent to a heavily restored molar
(Photo courtesy: Professor Camile Farah, Perth Oral Med-
icine & 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
Fig. 38 Ornamental ink tattooing involving the mandib-
ular 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 tat-
toos 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 evi-
dent 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, treat-
ment is not indicated. However, if treatment is
requested, low-energy lasers can be used to
remove the tattoos (Yilmaz et al. 2010). Sub-
epithelial 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 exci-
sion 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.
E.T. Stoopler and F. Alawi
2016). Examples include lead, mercury, silver,
and bismuth, among others. Exposure to these
metals most commonly occurs through continual
ingestion of contaminated drinking water or
foods, such as fish and seafood, or through occu-
pational exposure. In most cases, the discoloration
appears as a black-blue line that follows the out-
lines of the marginal gingiva (Alawi 2013;
Hassona et al. 2016). This is known as a Burton
or Burtonian line in individuals with chronic 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 reac-
tions 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 long-
lasting systemic and neurologic effects. Chela-
tion 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 ethylenedia-
minetetraacetic acid (EDTA) is also
recommended for lead poisoning. A mono-
isoamyl 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).
Pigmented Lesions of the Oral Mucosa
Conclusion and Future Directions
Melanin-associated pigmented lesions of the oral
mucosa can range from innocuous findings to life-
threatening conditions. It is important for oral
health-care providers to be familiar with the
range of clinical phenomena associated with
these types of pigmented lesions that affect both
the oral cavity and cutaneous surfaces. As under-
standing of genetics associated with melanogene-
sis and human biology are further refined, targeted
gene therapy and development of novel immuno-
therapeutics will potentially improve detection,
treatment, and prognosis of life-threatening mela-
nin-associated pigmentation disorders, such as
melanoma.
Cross-References
▶ Cutaneous pathology of the Head and Neck
Region
▶ Gingival Pathology
▶ Head and Neck Malignancies
▶ Oral Lichen Planus
▶ Oral Manifestations of Systemic Diseases and
their Treatments
▶ Oral Mucosal Malignancies
▶ Paediatric Oral Medicine
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