Erythroplakia is similar to leukoplakia except that it has a definite erythematous component. The distinction is important, since about 90% of cases of erythroplakia are either dysplasia or carcinoma. Squamous cell carcinoma accounts for 90% of oral cancer. Alcohol and tobacco are the major epidemiologic factors. The differential diagnosis may include oral candidiasis, necrotizing sialometaplasia, pseudoepitheliomatous hyperplasia, median rhomboid glossitis, and vesiculoerosive inflammatory disease such as erosive lichen planus. This should not be confused with the brown-black gingival melanin pigmentation—diffuse or speckled—common in nonwhites, blue-black embedded fragments of dental amalgam, or other systemic disorders associated with general pigmentation (neurofibromatosis, familial polyposis, Addison's disease). Intraoral melanoma is extremely rare.

Any erythroplakic or enlarging leukoplakic area should have an incisional biopsy or an exfoliative cytologic examination done by the clinician who will direct management of a cancer if one is discovered. Specialty referral should be sought early both for diagnosis and treatment. Intraoral staining with 1% toluidine blue may aid in selection of the most suspicious biopsy site. A systematic intraoral examination—including the lateral tongue, floor of the mouth, gingiva, buccal area, palate, and tonsillar fossae—and palpation of the neck for enlarged lymph nodes should be part of any general physical examination, especially in patients over 45 who smoke tobacco or drink immoderately. Indirect or fiberoptic examination of the nasopharynx, oropharynx, hypopharynx, and larynx should also be done by an otolaryngologist–head and neck surgeon or radiation oncologist. Fine-needle aspiration biopsy may be indicated if an enlarged lymph node is found.

Early detection of squamous cell carcinoma is the key to successful management. Lesions less than 4 mm in depth have a low propensity to metastasize. Most patients in whom the tumor is detected before it is 2 cm in diameter are cured. Small lesions are best treated with surgical excision, often with a laser. Radiation is an alternative but is associated with xerostomia, osteonecrosis of the mandible, and inability to use a curative dose again in the treatment field. Large tumors nevertheless are usually treated with a combination of resection and irradiation. Reconstruction, if required, is done at the time of resection and can involve the use of myocutaneous flaps or vascularized free flaps without bone. A number of clinical trials have suggested a role for beta-carotene, vitamin E, and retinoids in producing regression of leukoplakia and reducing the incidence of recurrent squamous cell carcinomas. This area is under intense study.