pigmented Lesions of the Oral
Mucosa
Mohamed Ismail Assadawy
Lecturer of Oral medicine , Periodontology ,Oral diagnosis and Oral
radiology

Oral pigmentation
Pigmentation is defined as the process of deposition of pigments in tissues. Various diseases can lead to
varied colorations in the mucosa. Pigmented lesions of oral cavity are due to
the oral mucosa and perioral tissues can assume a variety of discolorations, including brown, blue, gray,
and black
oral pigmentation ranging from a focal macule to broad, diffuse tumefactions. the specific hue, duration,
location, number, distribution,size, and shape of the pigmented lesion may also be of diagnostic
importance

Etiology
increase of melanin production
Increased number of
melanocytes (melanocytosis)
Deposition of accidentally
introduced exogenous materials

Classification
of pigmented
disease
Physiologic or pathologic
Endogenous or exogenous
Reversible or irreversible
melanocytic or nonmelanocytic
Benign or malignant
focal, multifocal, or diffuse in its presentation.
Iatrogenic :Exogenous . chronic

Focal pigmented lesions. Algorithm illustrating clinical procedures needed to segregate and
diagnose common focal pigmented lesion

Multifocal and diffuse pigmented lesions. Algorithm
illustrating the clinical presentation of pigmented lesions
with accompanying habits, endoscopic features, and

Oral melanoma

Bilateral oral melanoacanthoma in an Indian boy

oral compound nevus of retromolar

Oral melanotic macule gingiva

Ephelis or freckles of the lower vermilion border. Brown pigmented macule with
circumscribed borders on the left lower vermilion border usually occur on sun
exposed area

a melanotic macule does not become darker with continued sun
exposure. Unlike ephelides

Pretreatment amalgam tattoo on the keratinized

. A. Ulcerative lesions involving buccal mucosa in a
patient affected by OLP.
B. OPP disclosed after inflammation resolution

Smokers melanosis

Hard palate hyperpigmentation secondary to
chronic chloroquine

Imatinib‐induced pigmentation of the palate. A 65‐year‐old white female treated with imatinib for
gastrointestinal stromal tumor. Courtesy of Dr. Suman Sra,private practice, San Jose, CA, USA

Peutz-Jeghers Syndrome (Perioral Lesions)
© Springer Science+Business Media

Addison’s disease. (A) Patchy brown areas of pigmentations in the labial mucosa of an
individual with Addison’s disease. Courtesy of Dr. Jose Castillo, School of Dentistry, University
Mayor, Santiago, Chile

Conditions with high ACTH and
hyperpigmentation

Laugier–Hunziker pigmentation. Multiple pigmented macules were observed in this healthy female
who underwent colonoscopy and laboratory studies that ruled out Peutz–Jeghers syndrome and
Addison’s disease. This multifocal pattern of pigmentation is reminiscent of Peutz–Jeghers
syndrome.

Common Causes of Endogenous Oral and Perioral
Discoloration

Sources of Exogenous Oral and Perioral Pigmentation

Lesions that May Be Associated with Oral Mucosal
Discoloration

How the
discoloration
occurs?
Overproduction of melanin may be caused by a variety of mechanisms, the
most common of which is related to increased sun exposure. intraorally,
hyperpigmentation is more commonly a consequence of physiologic or
idiopathic sources, neoplasia, medication or oral contraceptive use, high
serum concentrations of pituitary adrenocorticotropic hormone (ACTH),
postinflammatory changes, and genetic or autoimmune disease
melanin is synthesized within specialized structures known as melanosomes.
melanin is actually composed of
eumelanin, which is a brown-black pigment, and pheomelanin, which has a
red-yellow color
melanosis is frequently used to describe diffuse hyperpigmentation

Etiology of Multifocal, Diffuse, or Generalized
Mucocutaneous Melanosis

Pigmentation diagnosis.

Diagnosis of perioral and oral mucosal
pigmented disease
• Patient bio especially the race
• Clinical oral and with or without systemic manifestation
• clinical tests, including diascopy, radiography .
• blood tests
• dermascopy, also known as epiluminescence microscopy for melanocytic lesions. although
current instrumentation is designed primarily for the study of cutaneous pigmentation,
several studies have described the use of dermascopy in the evaluation of labial and anterior
lingual pigmentation
• binocular stereo microscopes with or without the assistance of digital technology and
imaging software. this diagnostic technique has been shown to be effective in discriminating
melanocytic from nonmelanocytic lesions and benign versus malignant melanocytic
processes.

AI assisted
diagnosis
• the dermoscope and its associated intelligent dermoscopy
software) have been quick to become necessary medical tools
for the examination of all types of pigmented conditions.
Due to the strong associations with artificial intelligence in
dermatology, big data, interoperability, data
security and cloud-based software, digital dermoscopy
tools are set to evolve and improve at an impressive rat

Focal melanocytic Pigmentation
Freckle/Ephelis
Oral/Labial
Melanotic Macule
Oral
Melanoacanthoma
Melanocytic nevus
Malignant Melanoma

Focal lesions of clinical similarities
Melanotic macules, which consist of increased melanin, without
increased numbers of melanocytes.
Ephelides with sun exposure change in the amount of melanin and
consequently color, but melanotic macules do not.
 Melanoacanthomas – rare acquired brown to black, usually single,
benign areas of pigmentation of the mucosa, which can arise suddenly
and enlarge, commonly seen on the buccal mucosa of women of
African
heritage. Besides increased amount of melanin in the basal layer they
also typically show dendritic cells with melanin and eosinophils in the
upper epithelium. They may be melanotic macules that appear
suddenly

Melanotic macule
• Definition: Melanotic macule is an acquired, small, flat, brown to brown-black, asymptomatic, benign lesion,
unchanging in character.
Prevalence (approximate): 1 in 1000 adults.
Age mainly affected: Adults.
Gender mainly affected: F > M.
Etiopathogenesis: The oral melanotic macule is a focal increase in melanin deposition. Labial melanotic
macule (on the lip vermilion) is regarded as a distinct entity.
Melanotic macules are usually seen in isolation but may also be seen in:
• Peutz-Jeghers syndrome – an autosomal dominant trait related to serine/threonine kinase gene,
characterized by mucocutaneous melanotic macules, especially circumorally and hamartomatous intestinal
polyposis mainly in the small intestine, which rarely undergo malignant change but can produce
intussusception (obstruction). The risk of gastrointestinal, pancreatic, breast and reproductive carcinomas
is slightly increased
• Laugier–Hunziker syndrome – a benign condition of labial, oral, skin and nail hyperpigmentation Genital
involvement is not uncommon.
• HIV infection – most are related to primary adrenocortical deficiency or to zidovudine therapy

• History
Asymptomatic oral melanotic macules unchanging in character.
• Clinical features
Most are solitary and seen in white adults and their color ranges from brown to black. Many
macules occur on the vermilion border of the lower lip as solitary lesions (labial melanotic
macules). Intraorally, the
anterior gingivae, buccal mucosa, and palate are the main sites, and more than one lesion may
be detected The typical macule is a small well-demarcated, uniformly tan to dark brown, round or
oval discoloration < 7 mm diameter

.
Differential diagnosis: Tattoos, nevi, melanoma.
Biopsy/histopathology may be indicated if the lesion clinically resembles early melanoma,
especially if it develops rapidly.
Histopathologically
the stratified squamous epithelium is normal apart from increased pigmentation within the
keratinocytes of the basal and parabasal layers, accentuated at the tips of rete ridges. There is
negative staining for HMB- 45 (homatropine methylbromide) while nevi are positively
staining. There are no nevus cells or elongated rete ridges. There is melanin in the epithelial
basal layer and/or upper lamina propria. Deposits may also be seen within subepithelial
stroma (melanin incontinence), perhaps within macrophages or melanophages. Brown malinin
deposits can be differentiated from iron deposits by their association with erythrocytes rather
than with basal layer epithelial cells. There is no underlying inflammatory response

Management
The intraoral melanotic macule has no malignant transformation
potential, but an early melanoma could have a similar clinical appearance, so lesions
of recent onset, large size, irregular pigmentation, unknown duration, or enlarging
should be excised and examined histopathologically. No treatment is required
otherwise, except for cosmetic considerations (excision or removal by laser or hidden
by lipstick).
Prognosis Excellent.

Malignant melanoma
• Definition: Malignant neoplasm of melanocytes.
Prevalence (approximate): Uncommon – probably 1.2 cases per
10 million population per year. Japan and Uganda are areas of higher
prevalence. Oral melanoma accounts for 0.2–8% of melanomas and
approximately 1.6% of all head and neck malignancies.
• The oral mucosa is primarily involved in less than 1% of melanomas.
Age mainly affected: Middle-aged and older.
Gender mainly affected: M > F.
Etiopathogenesis: Sunlight exposure is causal in skin melanomas,
which have increased in almost epidemic fashion over the past decades,
especially in fair-skinned peoples.
• The cause of oral melanoma, however, is unknown and no link has been
established with chemical or physical trauma, tobacco use, betel chewing
or oral hygiene.
• Most oral melanomas are thought to arise de novo. Though oral nevi are
potential sources of some melanomas they are usually benign. Even blue
nevi, which are more common on the palate – the site of predilection for
melanoma – rarely undergo malignant transformation

Diagnostic features
History: Melanomas are usually symptomless in early stages; later
swelling, tooth mobility, or bleeding may appear.
Clinical features
The most common oral locations are the palate and maxillary gingiva.
Metastatic melanoma most frequently affects the mandible, tongue, and
buccal mucosa.
Oral melanoma often is overlooked or clinically misinterpreted as a
benign pigmented process until it is well advanced and it frequently
presents with metastases in lymph nodes, liver and lungs. Radial
(horizontal spread) and vertical (infiltrative) extension is common at the
time of diagnosis.
Pigmented solitary small brown or black macules 1.0 mm to 1.0 cm
or larger are found They grow rapidly, initially spreading radially and
superficially, later become increasingly pigmented, nodular, deeply
invasive and with satellite lesions. Up to 10% are non-pigmented

Clinical presentation of cases, a diffuse and painless asymptomatic swelling (approximately 3.0
cm of size) covered by erythematous lining mucosa. The tumor extended to the oropharynx
region and caused difficulty in swallowing and phonation. (B) the patient presented a small
asymptomatic sessile nodule, 0.5 cm, bleeding on palpation, in the region of the incisive papilla
between lower central incisors with a clinical diagnosis of pyogenic granuloma. (C), the patient
presented an asymptomatic swelling showing areas of ulceration in the upper left alveolar ridge
Amelanotic melanoma

Occasionally melanomas are nodular ab initio with deep
spread,or are multiple or large. Features suggestive of
malignancy include
a rapid increase in size, change in color, ulceration, pain,
bleeding,
the occurrence of satellite pigmented spots, or regional
lymph node enlargement.
Differential diagnosis: Melanotic macule, nevus,
tattoos, melanoacanthoma and Kaposi sarcoma.
Rubbing with a cotton pledget may elicit brown
pigmentation

Histology:
may show anaplastic spindle-shaped or squamoid cells. The
epithelium is abnormal, with large atypical melanocytes and
excessive melanin. The melanoma cells have large nuclei, often with
prominent nucleoli, and show nuclear pseudoinclusions due to
nuclear membrane irregularity. The abundant cytoplasm may be
uniformly eosinophilic or optically clear. Occasionally, the cells
become spindled,a finding interpreted as a more aggressive feature.
However, the histology is quite varied and staining with dopa or
antibodies may be required to help the diagnosis.
Melanoma stains positively with S100, tyrosinase, Mart-1/melan-A,
vimentin, microphthalmic transcription factor, and homatropine
methylbromide (HMB-45).
Immunohistochemistry:
though helpful to differentiate melanoma from other tumors, cannot
differentiate from nevus (usually atypical nevus)

Imaging modalities in melanoma
• Imaging is needed to exclude invasion. Contrast-enhanced CT
can be used to determine the extent of the melanoma and
whether local, regional, or lymph node metastasis is present.
MRI is used to diagnose melanoma in soft tissue.
• Bone scanning with gadolinium-based agents and chest
radiography can be beneficial in assessing metastasis.
Positron emission tomography (PET) has poor results in
distinguishing melanoma from nevi. However, combined PET-
CT may have diagnostic value

Melanoma management
•
The optimal treatment is surgery with neck dissection if regional lymph nodes are involved.
Prophylactic neck dissection is not advocated as a treatment. Early surgical intervention when local
recurrence is detected
enhances survival, because dismal outcomes are associated with distant metastasis.
•
Radiation and chemotherapy are unhelpful. However, although radiation alone is
reported to have questionable benefit (particularly in small fractionated doses), it is a valuable
adjuvant in achieving relapse free survival when high-fractionated doses are used.
• Drug therapies
used in the treatment of cutaneous melanoma (dacarbazine in conjunction with interleukin-2 (IL-2)),
and immunotherapy, are of questionable benefit in oral melanoma. There are anecdotal reports of
benefit from
interferon alfa (INF-A).
• Many centers, however, follow surgery with IL-2 adjunctive therapy to prevent or limit recurrence

Melanoma prognosis
• The prognosis is poor and worse than skin melanomas, unless
detected
very early, but many patients present in advanced stage with
involvement of cervical nodes and distant metastases to lung or
liver. The five-year survival rate is generally 5–50%.
• Tumor thickness or volume (Clark and Breslow indices) and lymph
node metastasis are less reliable prognostic indicators than they
are in skin (where lesions thinner than 0.75 mm rarely
metastasize)

Multifocal/diffuse Pigmentation
Physiologic
Pigmentation
drug-induced
Melanosis
smoker’s Melanosis
Postinflammatory
(inflammatory)
hyperpigmentation
Melasma
(Chloasma)
melanosis
associated with
systemic or genetic
disease
hemoglobin and
iron associated
Pigmentation
drug-induced
Pigmentation

Medications Associated with Mucocutaneous
Pigmentation

Melanosis associated with systemic or genetic disease
hypoadrenocorticism
(adrenal insufficiency,
Addison's disease)
Cushing’s
syndrome/Cushing’s disease
hyperthyroidism (graves’
disease
Primary Biliary Cirrhosis
Vitamin B 12 (Cobalamin)
defciency
Peutz-Jeghers syndrome
hiV/aids-associated
Melanosis
Laugier-hunziker
Pigmentation

gastrointestinal
disease, cancer
susceptibility, and
mucocutaneous
pigmented macules
triats
Peutz-Jeghers syndrome
Cowden syndrome
the allelic bannayan-riley-ruvalcaba
syndromes
lhermitte-duclos syndromes)
cronkhite-Canada syndrome.

Café au Lait Pigmentation
Diseases Commonly Associated with Café au Lait
Pigmentation

Depigmentation ( Vitiligo )
• Vitiligo is a relatively common, acquired, autoimmune disease that is
associated with hypomelanosis.
the pathogenesis of vitiligo is multifactorial, with both genetic and environmental factors
likely to play a role in disease pathogenesis. identified a single nucleotide polymorphism in
a vitiligo-susceptibility gene that is also associated with susceptibility to other autoimmune
diseases, including diabetes type 1, systemic lupus erythematosus, and rheumatoid arthritis.
Additional putative vitiligo-susceptibility genes have been mapped to various other
chromosomal regions

•Clinical presentation
• Age at any age but common at second decade
• Sex no sex predilection
• site at any site occur bilaterally on the lip (lip vitiligo). the skin and hair of most of the body may
lose its pigmentation (vitiligo universalis)
• Shape: vitiligenous lesions often present as well-circumscribed, round, oval or elongated, pale or
• white-colored macules that may coalesce into larger areas of diffuse depigmentation. As the
• disease progresses, additional areas of involvement may become apparent.
• Vitiligo may also arise in patients undergoing immunotherapy for the treatment of malignant
melanoma

pathology
microscopically, there is a complete loss of melanocytes and
melanin pigmentation in the basal cell layer. the use of
histochemical stains such as Fontana-masson will confirm,,the
absence of melanin.
Management
topical corticosteroids and topical or, more commonly, systemic
photochemotherapies (psoralen and ultraviolet a exposure) have
proven to be effective nonsurgical therapies
labial vitiligo is more resistant to the typical treatments used for
cutaneous vitiligo. due to a lack of hair follicles, the lips do not have a
reservoir of melanocytes that can be stimulated to produce pigment.,
surgical intervention may be the only option .

• focal areas of depigmentation. in other patients, an entire
segment on one side of the body may be affected. in
occasional patients, the skin and hair of most of the body
may lose its pigmentation (vitiligo universalis).
in most cases, vitiligo is characterized by bilateral,
symmetric areas of relatively generalized hypomelanosis.
the vitiligenous lesions often present as well-circumscribed,
round, oval or elongated, pale or white-colored macules
that
may coalesce into larger areas of diffuse depigmentation.
as
the disease progresses, additional areas of involvement
may
become apparent
Depigmentation in palate

Management ofmucocutaneous pigmented disease
Treatment modality depends on lesion type and behavior
Cause modification or elimination
surgical intervention is less of an option for the treatment
 laser therapy: Various types of lasers have been used, including
superpulsed co2, Q-switched nd-yag, and
Q-switched alexandrite lasers.

cryotherapy have been used to successfully treat
such cases.
phototherapy have also been employed, including
intense pulsed light. and fractional
photothermolysis.
 bleaching creams :a combination of 4%