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.

Clinical Features

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).

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 rare condition, Bandler syndrome, may feature melanotic macules of the oral mucosa and perioral region. This syndrome includes hemangiomas of the small intestine plus mucocutaneous pigmentation.

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.

Histopathology

Microscopically, melanotic macules are characterized by melanin accumulation in basal keratinocytes and normal numbers of melanocytes (Fig. 5-9). Melanophagocytosis is typically seen within the lamina propria.

Café-au-Lait Macules

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 p21^ras 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/>