Squamous cell head and neck cancers can be divided into well-differentiated, moderately well-differentiated, and poorly differentiated categories. Patients with poorly differentiated tumors have a worse prognosis than those with well-differentiated tumors. For nasopharyngeal cancers, the less common differentiated squamous cell carcinoma is distinguished from nonkeratinizing and undifferentiated carcinoma (lymphoepithelioma) that contains infiltrating (bystander) lymphocytes.

Salivary gland tumors can arise from the major (parotid, submandibular, sublingual) or minor salivary glands (located in the submucosa of the upper aerodigestive tract). Most parotid tumors are benign, but half of submandibular and sublingual gland tumors and most minor salivary gland tumors are malignant. Malignant tumors include mucoepidermoid and adenoidcystic carcinomas and adenocarcinomas.

The mucosal surface of the entire pharynx is exposed to alcohol- and tobacco-related carcinogens and is at risk for the development of a premalignant or malignant lesion, such as erythroplakia or leukoplakia (hyperplasia, dysplasia), that can progress to invasive carcinoma. Alternatively, multiple synchronous or metachronous cancers can develop. In fact, patients with early-stage head and neck cancer are at greater risk of dying of a second malignancy than of dying from a recurrence of the primary disease.

Second head and neck malignancies are not therapy-induced; they reflect the exposure of the upper aerodigestive mucosa to the same carcinogens that caused the first cancer. These second primaries develop in the head and neck area, the lung, or the esophagus.

Chromosomal deletions and other alterations, most frequently involving chromosomes 3p, 9p, 17p, and 13q, have been identified in both premalignant and malignant head and neck lesions, as have mutations in tumor suppressor genes, commonly the p53 gene. Amplification of oncogenes is less common, but overexpression of PRAD-1/bcl-1 (cyclin D1), bc1-2, transforming growth factor β, and the epidermal growth factor receptor have been described. The latter finding correlates positively with tumor size and poor outcome and is a target for experimental treatments.

Resected tumor specimens with histopathologically negative margins (“complete resection”) can have undetectable residual tumor cells with persistent p53 mutations at the margins. Thus, a tumor-specific p53 mutation can be detected in some phenotypically “normal” surgical margins, indicating residual disease. Patients with such submicroscopic marginal involvement may have a worse prognosis than patients with negative margins.