Pigmented oral mucosal lesions can be divided into two fundamental groups: those containing melanin and those containing other pigments. The latter would include discolorations associated with drug ingestion, metal implantation, and heavy-metal ingestion/intoxication. Breakdown products from extravascular blood due to trauma or blood dyscrasias (see Chapter 4) can also discolor oral mucosa. Pigmented lesions, which range from trivial to serious (melanoma), can be confused with each other clinically, necessitating careful evaluation.
Melanin-producing cells (melanocytes) have their embryologic origin in the neural crest. These cells migrate to epithelial surfaces and reside among basal cells. They have numerous dendritic processes that extend to adjacent keratinocytes. Organelles representing packaged granules of pigment known as melanosomes are produced by these melanocytes. These melanosomes are not ordinarily retained within the melanocyte itself but, rather, are delivered to surrounding keratinocytes and occasionally to subjacent macrophages. Light, hormones, and genetic constitution influence the amount of pigment produced.
Melanocytes are found throughout the oral mucosa but go unnoticed because of their relatively low level of pigment production (Fig. 5-1). They appear clear with nonstaining cytoplasm on routine histologic preparation. When focally or generally active in pigment production or proliferation, they may be responsible for several different entities in the oral mucous membranes, ranging from physiologic pigmentation to malignant neoplasia.
A relative of the melanocyte, the nevus cell, is responsible for pigmented nevi. Nevus cells, although morphologically different from melanocytes, possess the same enzyme, tyrosinase, which is responsible for conversion of tyrosine to melanin in the melanosome organelle.
Oral melanin-based pigmentations range from brown to black to blue, depending on the amount of melanin produced and the depth of the pigment relative to the surface. Generally, superficial pigmentation is brown, whereas more deeply located pigmentation is black to blue. Darkening of a preexisting lesion that has not been stimulated by known factors suggests that pigment cells are producing more melanin and/or invading deeper tissue.
Physiologic pigmentation is symmetric and persistent and does not alter normal architecture, such as gingival stippling (Fig. 5-2). This pigmentation may be seen in persons of any age and is without gender predilection. Often the degree of intraoral pigmentation may not correspond to the degree of cutaneous coloration. Physiologic pigmentation may be found in any location, although the gingiva is the most commonly affected intraoral tissue. A related type of pigmentation, called postinflammatory pigmentation, is occasionally seen after mucosal reaction to injury (Fig. 5-3). Occasionally in cases of lichen planus, areas surrounding active disease may eventually show mucosal or postinflammatory pigmentation.
Abnormal melanin pigmentation of oral mucosa has been linked to cigarette smoking and has been designated smoking-associated melanosis or smoker’s melanosis. The pathogenesis is believed to be related to a component in tobacco smoke that stimulates melanocytes. Female sex hormones are believed to be modifiers in this type of pigmentation because women (especially those taking birth control pills) are more commonly affected than men. Smoking up to nine cigarettes per day has been sufficient to produce gingival melanin deposition.
The anterior labial gingiva is the region most typically affected, where brownish color can vary from subtle to obvious. Palate and buccal mucosal pigmentation has been associated with pipe smoking. In India, the use of smokeless tobacco forms has been linked to oral melanosis, particularly among alcoholics. In smoking-associated melanosis, the intensity of pigmentation is time and dose related (Fig. 5-4).
With cessation of smoking, improvement is expected over the course of months to a few years. Smoker’s melanosis, per se, appears to be of little significance. However, it may potentially mask other lesions or may be cosmetically objectionable. In cases where surface irregularity or focally intense pigment deposits are noted, biopsy should be performed.
Oral melanotic macule (or focal melanosis) is a focal pigmented lesion that may represent (1) an intraoral freckle; (2) postinflammatory pigmentation; or (3) macules associated with Peutz-Jeghers syndrome, Bandler syndrome, or Addison’s disease (see Box 5-1).
Melanotic macules have been described as occurring predominantly on the vermilion of the lips and gingiva, although they may appear on any mucosal surface. They are asymptomatic and have no malignant potential.
When melanotic macules (freckles) are seen in excess in an oral and perioral distribution, Peutz-Jeghers syndrome and Addison’s disease should be considered (Box 5-2; Figs. 5-5 to 5-8). Peutz-Jeghers syndrome is a condition that is inherited in an autosomal-dominant pattern. In addition to ephelides or melanotic macules, intestinal polyposis is present. These polyps are regarded as hamartomas without, or with very limited, neoplastic potential. They usually are found in the small intestine (jejunum) and may produce signs and symptoms of abdominal pain, rectal bleeding, and diarrhea.
Addison’s disease, or primary adrenocortical insufficiency, may result from adrenal gland infection (tuberculosis), autoimmune disease, or idiopathic causes. With reduced cortisol production by the adrenals, pituitary adrenocorticotropic hormone (ACTH) and melanocyte-stimulating hormone (MSH) increase as part of a negative feedback mechanism. Overproduction of both ACTH and MSH results in stimulation of melanocytes, leading to diffuse pigmentation of the skin. Oral freckles and larger melanotic macules occur with generalized pigmentation. Other presenting signs and symptoms of this syndrome include weakness, weight loss, nausea, vomiting, and hypotension.
Pigmented macules have been described in association with two other rare syndromes. One includes soft tissue myxomas and endocrinopathies (myxoma syndrome). Oral, cutaneous, and cardiac myxomas may be seen in this autosomal-dominant syndrome. The other, known as Laugier-Hunziker syndrome or phenomenon, is a rare acquired pigmentary disorder that presents as lip, oral, or finger macules and subungual melanocytic streaks. Pigmentation of the conjunctiva and penis has been described in patients with this syndrome.
A melanotic macule that occurs exclusively on sun-damaged skin (especially the face and hands) is known as lentigo (plural, lentigines). These lesions are characteristically seen in older patients and appear as brown patches that are larger and darker than ephelides. The lesions are benign but may be cosmetically objectionable, in which case they may be treated with cryotherapy or laser vaporization.
These oral pigmentations must be differentiated from early superficial melanomas. They may be confused with blue nevi (palate) or amalgam tattoos. If they are numerous, Peutz-Jeghers syndrome, Addison’s disease, Bandler syndrome, and Laugier-Hunziker syndrome may be possible clinical considerations (Box 5-3).
Café-au-lait macules are discrete melanin-pigmented patches of skin that have irregular margins and a uniform brown coloration. They are noted at birth or soon thereafter and may also be seen in normal children. No treatment is required, but they may be indicative of a syndrome of greater significance (Box 5-4).
Individuals with six or more large café-au-lait macules (>0.5 cm diameter prepubertal, >1.5 cm diameter postpubertal) should be suspected of having neurofibromatosis (NF) (Fig. 5-10). Two forms of this autosomal-dominant disorder affect 100,000 people in the United States: neurofibromatosis 1 (NF1; previously called von Recklinghausen’s disease) and neurofibromatosis 2 (NF2; formerly known as acoustic neurofibromatosis). Although some overlapping features are known, the two conditions are distinct clinically and genetically. NF1 is a relatively common disorder affecting 1 in 3000 individuals. Approximately 50% of cases are inherited, and the remainder represent spontaneous new mutations. The condition is characterized by numerous neurofibromas of the skin, oral mucosa, nerves, and central nervous system, and occasionally the jaw. Axillary freckling (Crowe’s sign) accompanied by the presence of six or more of these macules is regarded as pathognomonic for NF1. The genetic abnormality involves the neurofibromin gene located on chromosome 17q11.2. This tumor suppressor gene encodes for neurofibromin protein, which downregulates the function of the p21ras protein. NF2 is characterized by bilateral acoustic neuromas, one or more plexiform neurofibromas, and Lisch nodules. The condition is caused by a mutation in the NF2 tumor suppressor gene located on chromosome 22q12 that encodes for the merlin protein, which, in turn, shows structural similarity to a series of cytoskeletal proteins. The normal function of merlin is not known.
Café-au-lait macules may be associated with Albright’s syndrome (polyostotic fibrous dysplasia, endocrine dysfunction, precocious puberty, café-au-lait macules), Noonan syndrome, Watson syndrome, Bloom syndrome, ring chromosome syndromes, and others. This sporadic disorder is co/>