11 Core Messages • Oropharyngeal squamous cell carcinoma (SCC) is increasing in incidence in the United States compared with other head and neck cancer sites. • High-risk human papillomavirus strains have been confirmed as a major etiologic factor in oropharyngeal SCC and are the principal cause of the rising incidence of the disease. • There is controversy concerning the best method of treatment for oropharyngeal SCC. However, there are several guidelines that a managing physician can follow to optimize oncologic and functional outcomes. • Minimally invasive surgical methods including transoral laser microsurgery and transoral robotic surgery are increasingly being viewed as viable treatment options for oropharyngeal SCC. Oropharyngeal squamous cell carcinoma (SCC) is a highly lethal and debilitating disease that is increasing in incidence compared with other head and neck cancer (HNC) sites. The critical location of this cancer creates a burden of disease which is greater than the numbers would indicate because of high treatment-related morbidity, including difficulties with speech and swallowing, malnourishment, tooth loss, chronic pain, reduced shoulder mobility, reduced quality of life, and altered physical appearance. These morbidities often require ongoing medical treatment long after the cancer is treated to preserve health and quality of life. Current trends in the management of oropharyngeal SCC are focused on determining whether patients with certain subsets of disease can undergo less-intensive therapy while providing adequate oncologic control and minimizing long-term morbidity. The oropharynx is an anatomically distinct region with a cancer pathophysiology, presentation, and treatment that differentiates it from the more anterior oral cavity. Many nonhead and neck trained specialists and researchers and many large cancer databases fail to take this distinction into account and unfortunately combine oropharyngeal and oral cavity SCC cases, thereby weakening the conclusions that can be drawn from the data. It is therefore critical for head and neck specialists to train others in the relevant anatomy of the oropharynx to allow proper staging and disease reporting. The oropharynx is the posterior throat and consists of four subsites: the soft palate, lateral pharyngeal wall, posterior pharyngeal wall, and base of tongue. The soft palate is the superior margin of the oropharynx and extends from the posterior border of the bony palate to the posterior edge of the uvula. The lateral pharyngeal wall consists of the anterior tonsillar pillars (anterior pharyngeal arches), the palatine tonsils or tonsillar fossae, and the posterior tonsillar pillars (posterior pharyngeal arches). The posterior pharyngeal wall is contiguous with the posterior wall of the nasopharynx and hypopharynx and extends from the level of the soft palate superiorly to the cricoid cartilage inferiorly. The base of the tongue is the posterior one-third of the tongue extending from the anterior tonsillar pillar and circumvallate papillae anteriorly to the vallecula posteriorly. The base of the tongue often has lingual tonsils on its superior surface, which form the base of Waldeyer ring of pharyngeal lymphoid tissue. The oropharynx is bordered by two clinically relevant spaces that have treatment implications.1 The parapharyngeal space is lateral to the lateral oropharyngeal wall and consists of the parapharyngeal fat pad, pterygoid musculature, and branches of the internal maxillary artery and trigeminal nerve. Tumor invasion of this space may result in trismus, indicating late stage disease requiring multimodality therapy. The retropharyngeal space is located behind the pharyngeal constrictor muscles that make up the posterior pharyngeal wall. The retropharyngeal space consists of loose areolar connective tissue and lymph nodes that may be the first echelon of spread of tumors of the posterior tonsillar pillar and posterior pharyngeal wall. The retropharyngeal nodes may be difficult to access and remove with a standard neck dissection and may provide a conduit for spread to additional nodes in the cervical lymphatic chain contralateral to the primary tumor.2 The oropharynx plays a critical role in swallowing function with contributions from 20 paired muscle groups and 5 cranial nerves. The main swallowing function of the oropharynx is the safe transfer of the liquid or food bolus from the oral cavity to the upper esophagus in a rapid (< 500 ms) fashion that protects the airway from bolus penetration or aspiration. Oropharynx cancer and its treatment may result in the reduced swallowing function and safety. Approximately 5000 new cases of oropharyngeal SCC occur in the United States each year, of which 90% are SCCs.2 Like other HNC sites, traditional risk factors for oropharyngeal SCC include tobacco (all forms), marijuana, and alcohol. Unlike other HNC sites that are decreasing in incidence with the reduction in the prevalence of cigarette smoking, oropharyngeal SCC is increasing in incidence each year, especially in people younger than 45 years in Western societies. Recent evidence has confirmed that certain high-risk strains of human papillomavirus (HPV) are responsible for the increasing incidence of oropharyngeal SCC of the tonsil and tongue observed over the past 30 years. HPV subtype 16 is estimated to be responsible for up to 60% of SCCs of the tonsil and base of the tongue.3 HPV-related oropharyngeal SCC appears to be a unique molecular, epidemiological, and clinical entity (Table 11.1). HPV-related SCC appears to follow a distinct molecular pathway distinguishing it from traditional non-HPV SCC. Repeated tobacco and alcohol exposure cause mutational loss of the p16 and p53 genes as early neoplastic events in up to 80% of SCCs.4 In most cases of HPV-related head and neck squamous cell carcinoma (HNSCC), unmutated wild-type p53 is present, but degraded by the E6 protein, and p16 is overexpressed on tissue immunohistochemistry.5,6 Therefore, it has been suggested that HPV is the likely cause of HNSCC if the cancer demonstrates normal p53 without mutations, overexpression of p16, in-situ hybridization of HPV DNA, and/or the presence of HPV E6 and E7 RNA in microdissected tumor by quantitative reverse transcription-polymerase chain reaction in ratios of > 1 copy number per 100 tumor cells.5 Although more research is needed to ascertain the mode of transmission, high-risk HPV is a known cause of cervical cancer in women, and it is therefore assumed that HPV spreads to the throat through sexual contact. The commercially available vaccines can reduce infection by HPV strains most responsible for genital warts and cancer if given before the initiation of sexual activity. Presently, the vaccine is only being widely offered and covered by insurance for preadolescent and adolescent girls despite the fact that men also develop genital warts, are purveyors and reservoirs for the virus, and may develop HPV-related HNSCC. In fact, based on Surveillance Epidemiology and End Results data, there are more cancers of the tonsil and tongue regions each year in the United States, 60% of which are thought to be due to HPV, than there are cancers of the uterine cervix. Therefore, clinicians who treat these diseases hope that both boys and girls will have greater access to these HPV-prevention vaccines in the future. Table 11.1 Differences between HPV-Negative and HPV-Positive HNSCC
Oropharynx Cancer
Anatomy
Epidemiology
Factor | HPV-Negative HNSCC | HPV-Positive HNSCC |
Molecular factors | p53 mutational loss common Rb upregulated p16 underexpression D cyclin overexpression No HPV DNA/RNA | p53 wild-type present Rb downregulated p16 overexpression D cyclin underexpression HPV DNA (type 16 in > 85% of the cases) HPV E6 and E7 RNA |
Epidemiological factors | Heavy smoking Heavy alcohol use Low marijuana exposure Poor dentition Low oral sex exposure Older age (> 50 y) Lower socioeconomic status African race Deceasing incidence | No smoking at all Mild/moderate alcohol use High marijuana exposure Intact dentition High oral sex exposure Younger age (< 45 y) Higher socioeconomic status Caucasian race Increasing incidence |
Clinical factors | All head and neck sites Worse survival Radiation response unpredictable | Predominantly oropharynx (tonsil and tongue base) Better survival More radiosensitive |
HPV, human papilloma virus; HNSCC, head and neck squamous cell carcinoma; y, year(s).
The difference in the prognosis in HPV-positive oropharyngeal SCC compared with HPV-negative oropharyngeal SCC provides the strongest argument for the increased use of HPV testing of oropharyngeal tumors. A growing body of evidence has shown that patients who are HPV-positive have a better prognosis compared with patients who are HPV-negative regardless of the treatment method.7,8 A meta-analysis of 23 studies analyzing survival in 1747 patients with HNC stratified for HPV status found a hazard ratio of 0.72 (95% CI, 0.5–1.0) for overall survival in patients with HPV-positive oropharyngeal cancer and a hazard ratio of 0.51 (95% CI, 0.4–0.7) for disease-free survival in patients with HPV-negative oropharyngeal cancer.9 A study that assessed the HPV status of patients with oropharyngeal SCC undergoing a randomized trial of concurrent chemoradiation therapy found a significant 58% reduction in the risk of death 3 years after the treatment in the HPV-positive cohort while controlling for age, race, stage, tobacco exposure, and treatment received.10 Therefore, it is estimated that HPV-positive status in oropharyngeal SCC may lower the risk of overall mortality by 28 to 58%.
Differences in HPV rates have been proposed as a possible explanation for the higher death rate from HNC observed in blacks compared with whites. A retrospective review of a clinical trial of induction chemotherapy followed by concurrent chemoradiation therapy found significant racial differences in HPV positivity with 35% of the white patients having HPV-positive tumors compared with only 4% of the black patients.11 The lower median overall survival observed for blacks (20.9 months) compared with whites (70.6 months) was present only when HPV-positive cases were considered because whites with HPV-negative tumors had an equally poor survival compared with blacks.
Clinical Presentation
Oropharyngeal SCC is typically asymptomatic in its earliest stages. Therefore, a complete examination should be performed routinely by all general health care providers and oral health specialists as part of the routine physical examination. The soft palate, tonsillar region, and posterior pharyngeal wall can usually be adequately visualized with a tongue blade or retractor and light source. Visual inspection of the base of the tongue requires either a mirror or a fiberoptic scope; however, digital palpation for a firm or raised mass with a gloved finger can substitute if these are not readily available. Early lesions may appear as white or erythematous lesions with ulceration or exophytic growth. HPV-related lesions often have a exophytic, papillomatous, strawberry-like appearance as opposed to HPV-negative lesions that are often ulcerative (Fig. 11.1A, B). If the lesion can be sufficiently visualized, biopsy can be performed in the office with cupped forceps after applying a topical anesthetic spray. Lesions that are less accessible due to anatomy or patient cooperation may require directed laryngoscopy and biopsy in the operating suite.
Early symptoms of oropharyngeal tumors include chronic sore throat, odynophagia, and dysphagia, whereas late symptoms include neck mass, trismus, tongue or chin numbness, and weight loss. A thorough fiberoptic examination of the oropharynx is a necessary measure for any patient with persistent sore throat or swallowing difficulty lasting more than 2 weeks because most infectious causes should have resolved in that time frame. Patients with unilateral otalgia without ear pathology require a thorough oropharyngeal examination.
Regional nodal adenopathy is present in more than 50% of the patients with oropharyngeal SCC at presentation. In fact, an enlarged neck node is often the presenting sign of the disease. Therefore, a thorough oropharyngeal examination is the standard of care for any patient with enlarged cervical adenopathy. Radiographic imaging (e.g., computed tomography (CT) of neck with intravenous contrast) and fine-needle aspiration with cytological analysis is recommended for any large or suspicious lymph node that has failed to respond to an appropriate course of antibiotics or other conservative therapy. The presence of a cystic node on imaging strongly suggests an oropharyngeal primary tumor in cases of occult primary tumor (Fig. 11.2).
Figure 11.1 (A) Human papillomavirus (HPV)-associated oropharyngeal tumors may have a papillomatous, strawberry-like gross appearance, whereas (B) HPV-negative tumors are often endophytic and ulcerative.
