Oropharyngeal Cancer

Tobacco and Alcohol Use

Squamous cell carcinoma of the oropharynx has traditionally affected patients older than 50 years, and men more than women. Despite this generalization, over the past 30 years oropharyngeal cancer rates have been on the rise in both men and women under the age of 45 years. Both alcohol and tobacco use are long-known, well-defined risk factors for SCCs of the head and neck, including those arising within the oropharynx. Again, separating data regarding oral cavity tumors and oropharyngeal tumors within published series can be challenging given reporting methods, and results may overstate the role of tobacco and alcohol use in oropharyngeal malignant diseases. The two substances individually and together contribute to a field cancerization effect within the upper aerodigestive tract. The effect of alcohol consumption and cigarette smoking on oropharyngeal cancer risk is dependent on both the intensity and duration of use and was traditionally responsible for approximately 80% of oropharyngeal cancers, with a higher proportion in men than in women in one series.

A population-based study in Sweden compared 605 patients with head and neck cancer with 756 controls. A hazard ratio (HR) of 8.4 was seen with current smokers; this figure was increased by an earlier starting age, longer duration of smoking, greater lifetime total consumption, and increased intensity of daily tobacco use. Increasing alcohol intake, particularly more than 50 g per day, was also associated with an increased relative risk of head and neck cancer. A compilation of case-control studies places the tobacco-associated odds ratio at 2.13 for tobacco users when compared with never users, with the ratio doubling in persons who smoke more than 30 cigarettes per day or those who have smoked for more than 30 pack-years. Involuntary or secondhand tobacco exposure may also be a risk factor, particularly when the person has been exposed for more than 15 years, either at home or at work. Alcohol use increases the rate of oropharyngeal carcinomas in never smokers, prior smokers, and current smokers, and the risk decreases with cessation of alcohol use. Although use of either alcohol or tobacco alone elevates the risk of oral cavity and oropharyngeal cancer, there is a synergistic effect from the use of both simultaneously. The risk is calculated to be thirteenfold the expected risk of each used independently, creating an approximately fiftyfold greater risk for oral cavity and oropharyngeal cancer compared with that of nonsmokers and nondrinkers. Tobacco cessation decreased the risk of head and neck cancer by 40% in years 1 through 4, although the risk of head and neck cancers did not return to baseline until 20 years had elapsed after either tobacco or alcohol cessation.

Human Papillomavirus Infection

Additional behavioral risk factors have been described besides the well-established tobacco and alcohol use, and these risk factors correlate with an elevated risk of oral human papillomavirus infection (HPV). The role of HPV corresponds to the identified increase in head and neck cancer incidence seen in younger nonsmokers and nondrinkers. The increased incidence has been seen both in the United States and in European countries, despite the general trend of fewer head and neck cancers. This rise has been most marked among young patients in sites associated with HPV. HPV is a sexually transmitted disease recognized over the past several years as a risk factor for squamous cell carcinoma of the head and neck, particularly in the oropharyngeal subsite, although the connection was initially suggested in 1983. HPV has been implicated in approximately 25% of head and neck cancers based on polymerase chain reaction (PCR) detection of HPV DNA. This prevalence is site specific, with a significantly higher percentage of HPV-associated cancers in the oropharynx compared with the oral cavity or larynx. A recent meta-analysis found the overall prevalence of HPV in oropharyngeal cancers to have increased over time. Prior to 2000, the rate of positivity was 40.5%, increasing to 64.3% from 2000 to 2004 and 72.2% between 2005 and 2009. Evaluation of more distant time periods demonstrates an even lower rate of HPV involvement, with a 16.3% detection rate from 1984 to 1989, increasing to 71.7% from 2001 to 2004. These trends constitute a population-based HPV-positive increase of 225% over this time period, while the HPV-negative incidence dropped by 50%.

The link between HPV and oropharyngeal cancers is several-fold and mimics the lines of evidence associating HPV and cervical cancer. First, HPV has been identified in tumor cells of head and neck squamous cell carcinomas. HPV status is most commonly assessed by either immunohistochemistry for p16 or in situ hybridization for high-risk HPV subtypes. Both methods have demonstrated prognostic significance despite some studies suggesting a 15% to 20% false–positive and false–negative rates for p16 immunohistochemistry testing as a surrogate for HPV. Identified prevalence rates have varied, depending on the tumor subsite, sensitivity of the HPV detection method, and geographic location, with associated ethnic variance. HPV-16 is the most common HPV subtype associated with oropharyngeal SCCs, seen in 85% to 90% of HPV-associated cancers. The remainder are associated with high-risk HPV subtypes 18, 31, 33, and 35, which also play a role in the development of cervical cancer. Second, HPV-positive SCCs of the head and neck have viral characteristics concordant with HPV-associated carcinogenesis, including a high viral load and viral oncoprotein expression. The oncogenic function of these HPV-associated oncoproteins ultimately accounts for the different molecular alterations found in HPV-positive tumors compared with HPV-negative tumors.

Additional evidence for an HPV association includes significant links in case-control studies between HPV seropositivity and squamous cell carcinomas of the head and neck. A case-control study comparing 100 patients diagnosed with oropharyngeal cancer and 200 controls found oropharyngeal cancer to be closely associated with oral HPV-16 infection (odds ratio [OR], 14.6), oral infection with any of the HPV types (OR, 12.3), and seropositivity for the HPV-16 L1 capsid protein (OR, 32.2), strongly associating oral HPV with oropharyngeal cancer. Behavioral risk factors associated with oral HPV infection have also been correlated with an increased risk of oropharyngeal cancer. They include a high lifetime number of vaginal-sex partners and oral-sex partners. This correlation between HPV DNA in tumor specimens and lifetime sex partners has also been identified by others, as has age at first intercourse and genital warts. Patients with HPV-associated head and neck cancers also have an increased risk of anogenital cancers, of which cervical and anal cancers have been strongly associated with HPV infection, and vice versa. Again, this supports the influence of sexual behavior and HPV infection on oropharyngeal cancer risk.

Patients with HPV-associated oropharyngeal cancers tend to have distinct clinical and pathologic features compared with those with HPV-negative cancers ( Table 39.1 ). Besides the history of high-risk sexual behavior described above, patients with HPV-associated oropharyngeal cancers are more likely to be light users or nonusers of alcohol and tobacco, although this lack of connection has not been universally identified. Despite the apparent lack of association between HPV-associated oropharyngeal cancers and tobacco use, there is a correlation with marijuana use and its intensity and duration. Individuals with HPV-positive squamous cell carcinoma of the head and neck tend to be younger by approximately 5 years compared with patients who are HPV-negative. Pathologically, HPV-positive cancers are more likely to be poorly differentiated with basaloid features.

A meta-analysis of the prognostic impact of HPV in head and neck squamous cell carcinomas demonstrated that patients who were HPV-positive were likely to have improvements in rates of overall survival (OS) (hazard ratio [HR], 0.85) and disease-free survival (DFS) (HR, 0.62). Similar improvements in OS and DFS were identified specifically within the oropharyngeal subsite. Improved outcomes with HPV positivity were confirmed in an Eastern Cooperative Oncology Group (ECOG) Phase II multicenter trial in which higher response rates were seen after induction chemotherapy and after chemoradiation treatment. This led to a statistically improved OS and a lower risk of progression. Analysis of the subset of patients with stage III or IV oropharyngeal cancer in Radiation Therapy Oncology Group (RTOG) study 0129 found HPV status to be the major determinant of overall survival, followed by duration of tobacco use and tumor stage. Locoregional recurrences were reduced at 3 years (13.6% vs. 35.1%) in HPV-positive tumors, and OS was 82.4% versus 57.1%. Although the bulk of the survival difference was attributable to HPV-positivity, favorable prognostic features associated with the HPV-positive subgroup accounted for approximately 10% of the outcome difference.

Patients who are HPV positive also have a lower risk of second malignant tumors because such patients lack the field cancerization effect produced by alcohol and tobacco exposure. Given the different clinical, pathologic, and molecular characteristics, as well as the improved prognosis and treatment response seen in HPV-associated disease, HPV-positive and HPV-negative SCCs of the oropharynx have been recognized as distinct entities with the latest AJCC staging manual (see Staging section ).

Other Risk Factors

Numerous other potential risk factors have been described for oropharyngeal cancer and head and neck cancer in general.

Nutritional deficiencies, as signified by a body mass index decline before diagnosis, have also been associated with oral cancer risk. This was again seen primarily among individuals with active or prior alcohol and tobacco use. Poor oral hygiene, as measured by surrogates such as tooth loss and infrequent dental visits, also correlates with an elevated rate of oral and oropharyngeal carcinomas. In short, the family history, diet, nutritional status, and oral hygiene may all play a role in oropharyngeal carcinoma predisposition, but defining the impact of each of these in the setting of the more dominant risk factors of alcohol and tobacco use is challenging, particularly given the potential interplay between such factors.

A family history of head and neck cancer produces an odds ratio risk increase of 1.7, although this is only seen in subjects exposed to tobacco, suggesting that this factor may represent an environmental as much as a genetic influence. A majority of studies found that diets low in raw vegetables and citrus and noncitrus fruits have increased the oral cancer risk. These results seem to hold true even when studies have been controlled for alcohol and tobacco usage, although the effect on diet and nutritional deficiencies from heavy alcohol and tobacco abuse is substantial and such factors can be difficult to account for in case-control studies.

Pathologic Findings

Primary oropharyngeal tumors are almost exclusively squamous cell carcinomas (≈ 95% of tumors). Alternative pathologic types include melanoma ( eFig. 39.1 ), primary lymphoid malignant tumors ( eFig. 39.2 ), minor salivary gland tumors, sarcomas, and other oddities. Given the preponderance of SCC in this site, this chapter will refer to the evaluation and treatment of SCC unless another type is specifically indicated.

A substantial literature has been generated evaluating the histologic subtypes of SCC of the head and neck, the appropriate nomenclature for these tumors, and their clinical impact. Specific subtypes include the spindle cell variant characterized by noncohesive spindle cells, which closely resembles sarcoma microscopically. The basaloid squamous variant is a distinct subtype traditionally correlated with aggressive behavior and poor patient outcomes. However, the recent correlation of HPV-associated malignant disease with the basaloid subtype has shown that the basaloid group is a mixture of both HPV-16–positive and HPV-16–negative carcinomas. Because the HPV status imparts a substantially favorable influence on outcome, the implication is that the basaloid phenotype alone does not confer a worse clinical outcome. Angiolymphatic invasion and perineural invasion are both associated with increased rates of cervical nodal metastases and a worse prognosis.

The prototypical SCC of the head and neck, including the oropharynx, is moderately differentiated, with approximately 60% moderately differentiated, 20% well differentiated, and 20% poorly differentiated. Some studies have found tumor grade to be predictive of regional nodal metastasis and, subsequently, clinical outcome. The determination of tumor grade based on traditional cytologic and histologic features of differentiation is challenging to reproduce because of interobserver variability. As a result, the tumor grade seems to have limited prognostic value, particularly when compared with the clinical staging parameters. Undifferentiated carcinomas with a lymphoid stroma arising from the tonsil have biologic behavioral characteristics and an increased radiosensitivity that are more similar to undifferentiated nonkeratinizing nasopharyngeal carcinomas rather than conventional types of SCC. Again, this subtype seems to serve as a surrogate for HPV-positivity.

The discrepancy in the pathologic appearance and clinical behavior of oropharyngeal SCC is recognized in the the AJCC 8th edition, which comments that the “standard nomenclature is unsatisfactory in describing HPV-mediated p16+ oropharyngeal cancers.” Although frequently describes as “poorly differentiated” based on the high nuclear/cytoplasmic ratio, this is ultimately at odds with the improved prognosis associated with HPV-associated cancers. The terminology of “oropharyngeal squamous carcinoma, nonkeratinizing-type” is ultimately recommended to avoid the connotation of a more aggressive malignancy that the poorly differentiated descriptor implies. This also recognized that frank tumor keratinization and keratin pearls are typically not seen in HPV-mediated cancers.

Pathways of Spread

The oropharynx makes up the central portion of the upper aerodigestive tract, encompassing the tongue base, palatine (faucial) tonsils, inferior aspect of the soft palate, and posterior and lateral oropharyngeal walls (see Fig. 39.1 and Figs. 39.2 and 39.3 ). The anterior margins are the anterior tonsillar pillars, the hard-soft palate junction, and the circumvallate papillae of the tongue, placing the posterior third of the tongue within the oropharynx. Superiorly, the oropharynx is bounded by the inferior aspect of the soft palate, posteroinferiorly by the pharyngoepiglottic folds that lie approximately at the level of the hyoid bone, and inferiorly by the glossoepiglottic fold and vallecula. The lateral and posterior borders of the oropharynx are defined by the pharyngeal constrictor muscles and their overlying mucosa. Understanding the anatomy of the oropharynx is necessary when identifying the typical pathways of spread by oropharyngeal neoplasms.

Soft Palate

The soft palate is a mobile flap of soft tissue with a central aponeurosis that serves as the attachment point for several palatine muscles. Five muscles form the bulk of the posterior and lateral portions of the soft palate. These muscles (levator veli palatini and tensor veli palatini muscles, muscle of the uvula, palatoglossus muscle, and palatopharyngeal muscle) insert on the palatine aponeurosis, but have important attachments to the tongue base, posterolateral pharyngeal wall, and torus tubarius. The palatoglossus muscle and overlying mucosa form the anterior tonsillar pillar, which is the anterior-most part of the lateral oropharynx. The palatopharyngeal muscle, with its overlying mucosa, forms the posterior tonsillar pillar. The two pillars connect laterally and inferiorly with the lateral oropharyngeal wall.

The inferior aspect of the soft palate, which forms the upper portion of the oropharynx, is the site of the majority of soft palate tumors. The superior surface of the soft palate, part of the nasopharynx, is seldom a primary site of neoplasm. The soft palate also contains a substantial number of minor salivary glands. These glands are the site of origin for nonsquamous neoplasms of the soft palate.

A soft palate tumor can spread anteriorly to involve the hard palate. There is also potential for perineural spread along the greater and lesser palatine branches of the maxillary nerve superiorly into the pterygopalatine fossa ( Fig. 39.4 ). Further perineural spread from the pterygopalatine fossa can result in extension along branches of the maxillary division of the trigeminal nerve into the orbit via the inferior orbital fissure, into the central skull base via the foramen rotundum, and into the facial nerve and temporal bone via the nerve of the pterygoid canal (vidian nerve). This perineural spread can result in palsies of both the trigeminal and facial nerves. Patients with advanced disease and perineural spread may present with trismus resulting from involvement of the pterygoid muscles or branches of the trigeminal nerve.

Tonsillar Region

The palatine (faucial) tonsils consist of lymphoid tissue constrained within a fibrous capsule that projects into the oropharynx between the triangle formed by the anterior and posterior tonsillar pillars. The tonsillar fossa is bounded laterally by the superior pharyngeal constrictor muscle. The anterior and posterior tonsillar pillars consist of the mucosa overlying the palatoglossus and palatopharyngeal muscles, respectively. Squamous cell carcinoma is the most frequent neoplasm of the palatine tonsils, followed distantly by non-Hodgkin's lymphoma. Tumors within the tonsillar region can spread superiorly to the soft palate along the vertically oriented palatoglossus and palatopharyngeal muscles, as well as inferiorly to the tongue base and posterolaterally to the oropharyngeal wall (see Fig. 39.4 and 39.5 ).

The superior pharyngeal constrictor muscle, in addition to forming the posterior and lateral borders of the oropharynx, courses deep to the palatine tonsils as it extends anteriorly to insert on the pterygomandibular raphe. This fibrous raphe is a shared insertion site with the buccinator muscle, with the raphe extending to the medial pterygoid plates superiorly and the lingual cortex of the mandible inferiorly just posterior to the mylohyoid line. Tonsillar neoplasms that invade the superior pharyngeal constrictor muscle and involve the pterygomandibular raphe can spread anteriorly to the buccinator muscle and space, superiorly to the medial pterygoid plate and masticator space, and inferiorly to the lingual cortex of the mandible. Lateral extension of tumor allows its entry into the parapharyngeal space ( Fig. 39.6 ). Involvement of the parapharyngeal space by tonsillar neoplasms may result in spread to and along the styloglossus and stylopharyngeal muscles, which extend superiorly toward the skull base and attach to the styloid process. Lateral extension into the medial pterygoid muscle is often associated with involvement of the mandibular division (V3) of the trigeminal nerve. Involvement of V3 can allow perineural tumor spread inferiorly into the mandible along the inferior alveolar nerve and superiorly along the main trunk of V3 to the foramen ovale and cavernous sinus.

Oropharyngeal Wall

The posterior and lateral walls of the oropharynx are formed by the superior pharyngeal constrictor muscle and overlying mucosa. The deep aspect of the superior constrictor muscle is separated from the prevertebral fascia by a thin layer of retropharyngeal fat. Tumors within the posterior aspect of the oropharynx can extend through this layer of fat and fascia and into the prevertebral space (see Fig. 39.6 ). Advanced tumors can ultimately involve the vertebral column, although such spread is typically inhibited by the multiple intervening fascial planes and the longus colli and longus capitis muscles. Tumors of the posterolateral oropharyngeal wall can extend into the nasopharynx and hypopharynx by way of either mucosal or submucosal spread (see Fig. 39.6 ).

Tongue Base

The tongue base is separated from the oral tongue anteriorly by the circumvallate papillae. It extends posteriorly and inferiorly to terminate near the level of the hyoid bone (see Figs. 39.2 and 39.3 ). Laterally, it is separated from the palatine tonsils by the glossotonsillar sulcus. The lingual tonsils lie along the posterior surface of the tongue base. The lingual tonsils are variable in size and may be quite large in the first two decades of life and in patients with concurrent head and neck infections.

Neoplasms of the tongue base spread along several pathways as they increase in size. They may infiltrate along the intrinsic muscles of the tongue into the oral tongue and deep tongue musculature. It is especially important to identify involvement of the extrinsic muscles of the tongue (i.e., the hyoglossus, styloglossus, and genioglossus muscles) because this indicates a T4 lesion. Tumor may track superolaterally along the mylohyoid muscle to invade the lingual surface of the mandible. Deep anterior extension may also involve the hypoglossal or lingual neurovascular bundles. Tumor can track posteriorly along these nerves between the superior and middle pharyngeal constrictor muscles into the parapharyngeal and masticator spaces.

Base of tongue cancer can also spread superficially along the mucosa. Posteroinferior extension can involve the vallecula, lingual surface of the epiglottis, and pharyngoepiglottic folds ( Fig. 39.7 ). There may be invasion of the preepiglottic space whenever the vallecula or glossoepiglottic folds are involved.

Nodal Involvement

Nodal metastasis has been reported in 40% to 66% of patients presenting with soft palate carcinoma. Level II nodal involvement is most frequent, with extension into level III and IV nodes commonly seen. Level I, level V, and lateral retropharyngeal nodal involvement is uncommon. Lymph node metastasis from squamous cell cancer of the palatine tonsils is very common (69% to 74%) at the time of presentation. The incidence of nodal involvement at diagnosis in patients diagnosed with tongue base carcinoma has been reported to be between 64% and 78%. Bilateral nodal disease is commonplace with base of tongue cancer, especially in patients with tumors near or crossing the midline. The incidence of nodal involvement in patients with oropharyngeal wall squamous carcinomas has been reported to be between 57% and 60% ( eFig. 39.3 through eFig. 39.5 ). Radiographic involvement of the retropharyngeal nodes is present in 16% of all patients with oropharynx cancer, rising to 23% with pathologic nodal disease in other neck sites. With nodal involvement elsewhere in the neck, retropharyngeal nodal involvement varies by subsite and is identified in 13% of base of tongue tumors, 14% of tonsillar tumors, 38% of posterior pharyngeal wall tumors, and 56% of soft palate tumors. This has implications for both the primary treatment modality and the design of the radiation treatment volumes.

Patient Evaluation

A comprehensive history with an emphasis on head- and neck-related symptoms should be taken for all patients, and a detailed physical examination of the head and neck region should be performed ( Table 39.2 ). The examination should include a direct inspection of the oral cavity and proximal oropharynx; an indirect (mirror) or fiberoptic examination of the distal oropharynx, hypopharynx, nasopharynx, and larynx; careful palpation of the oral cavity and proximal oropharynx; and inspection and palpation of the cervical lymph nodes ( Fig. 39.8 ). Relaxing the sternocleidomastoid muscle by tilting the head slightly to the ipsilateral side allows easier palpation of the jugulodigastric nodes. Flexible fiberoptic nasopharyngoscopy is used as indicated by examination findings and the quality of the indirect examination.

Physical examination includes assessment of both the size and local extent of the primary tumor and the presence, size, and location of the cervical lymphadenopathy. The size of the primary tumor and nodal disease should be measured as this is the basis of the AJCC staging system for oropharyngeal cancers. Consideration should be given to documentation of the extent of disease prior to treatment with still photography and videography in the electronic medical record.

Additional staging information can be gleaned during the physical examination. Trismus, documented by measuring the distance between the upper and lower incisors, or alveolar ridges in edentulous patients, is a consequence of tumor invasion into the pterygoid musculature. Deviation of the tongue on protrusion suggests involvement of the deep or extrinsic muscles of the tongue or invasion or compression of the hypoglossal nerve (CN XII) (see eFig. 39.6 ). A detailed physical examination is especially important with oropharyngeal cancers because treatment-altering findings may manifest themselves on visual inspection, but not on radiographic evaluation, and can alter both radiation treatment coverage and staging. For example, subtle superficial mucosal extension of a tonsillar tumor onto the adjacent soft palate or retromolar trigone may only be apparent during direct inspection and must be documented. Such regions may be more apparent during radiation treatment at approximately 20 Gy to 30 Gy because “tumoritis” causes increased erythema of these regions compared with the surrounding normal tissue ( eFig. 39.7 ). With base of tongue tumors in particular, digital palpation is essential to determine the size and extent of local spread because these tumors are frequently not seen during or are underestimated by visual examination, especially if they are endophytic. All borders of the tumor must be determined precisely because this has a crucial impact on target volume delineation and treatment field arrangement. Precision in defining tumor borders becomes even more paramount in the intensity-modulated radiation therapy era. Detailed examination of the remainder of the head and neck is also important because of field cancerization and the risk of synchronous primary tumors.

Aside from a complete history and physical examination, the workup should include biopsy confirmation of the mass. Biopsy should be performed by the least invasive means possible and can include fine-needle aspiration of involved cervical nodes or biopsy of the primary site. In general, excisional biopsy of the primary site or involved lymph nodes is not recommended because of concerns about prolonged healing times that may delay definitive radiation and surgery-associated hypoxic changes.

Given the significant prognostic importance and the implications for clinical investigation, assessing oropharynx squamous cell cancers for HPV has become routine. Immunohistochemical staining for p16 is a readily available and a well-correlated surrogate for HPV, although interpretation requires some experience.

Imaging Studies

Imaging Technique

The development of multiple detector-row CT (MDCT) scanning in conjunction with helical acquisition techniques over the last decade has revolutionized the cross-sectional imaging of patients with head and neck cancer. The ability to obtain axial image information from 64 to 256 rows of detectors simultaneously allows rapid scanning of patients with almost no motion artifact. The multiple rows of detectors can produce 64 to 256 images simultaneously, each with a slice thickness of 0.5 mm to 0.625 mm. This enables acquisition of a three-dimensional volume of image data that can be processed into images of varying slice thicknesses generated in sagittal, coronal, or oblique imaging planes. These two-dimensional re-formations offer improved visualization of the three-dimensional extent of the primary neoplasm and involved cervical lymph nodes.

Because of the possibility that lower cervical and upper mediastinal nodes may be involved by tumor, it is important to start the CT acquisition just below the aortic arch at the level of the aortopulmonary window. The scans should extend superiorly to the level of the cavernous sinus and skull base foramina in order to detect perineural tumor spread along cranial nerve branches, invasion of the masticator and parapharyngeal spaces, and skull base invasion. Non–contrast-enhanced scans prior to contrast administration are rarely beneficial and do not need to be routinely obtained. Sufficient time must be allowed for the injected contrast material to enhance the primary tumor and lymph nodes before scanning begins. As a result, a scanner-specific time delay must be inserted between the start of the contrast injection and the initiation of the CT scan in order to obtain maximal enhancement, with the goal of providing differentiating tissue enhancement rather than vascular opacification. Tight compact bolus injection of the contrast medium (3 mL to 4 mL per second) offers superior enhancement of lesions. Bone and soft tissue reconstruction algorithms should both be obtained for maximal diagnostic information.

Magnetic resonance imaging protocols should be constructed in a similar manner to cover the region from the skull base and cavernous sinuses to the aortic arch. It is particularly important to obtain both high-quality non–contrast-enhanced T1- and T2-weighted images because these are often more helpful than contrast-enhanced images at defining the extent of the primary neoplasm and assessing nodal disease. Postcontrast-enhanced T1-weighted images obtained with fat suppression are helpful for identifying perineural tumor spread, skull base invasion, and deep spread to the masticator and parapharyngeal spaces, as well as for detecting intranodal tumor deposits. Because of the extensive pterygoid plexus of veins in the masticator space and normal enhancement of mucosal areas of the head and neck, contrast-enhanced scans are often challenging to interpret. These images must be carefully compared with non–contrast-enhanced images in the same plane.

Staging

The AJCC 8 ^th edition, published in 2017 and implemented on January 1, 2018, contains dramatic revisions of the oropharyngeal cancer staging system, particularly involving HPV-positive cancers. In the AJCC 7 ^th edition, oropharyngeal cancers were placed within the pharynx chapter, combined with nasopharyngeal and hypopharyngeal cancers. Secondary to the unique biologic behavior of HPV-positive oropharyngeal cancers compared with HPV-negative cancers of the oropharynx and other subsites, the prior staging system was found to have limited predictive value for overall outcomes. In particular, the 7 ^th edition oropharyngeal cancer algorithm poorly differentiated recurrence and survival outcomes between stages with a simultaneous numerical imbalance toward stage III and IV. Specifically, stages I, II, III, and IVA demonstrated no differences in 5-year OS, and stage III and IVA comprised 13% and 73% of all patients. As a result, the AJCC 8 ^th edition divided oropharyngeal cancers between high-risk HPV (HR-HPV)-associated oropharyngeal cancers and non–HPV-associated oropharyngeal cancers with the goal of improving outcome stratification by stage subgroup (hazard discrimination). To prognosticate these distinct disease entities better, the prior single pharynx chapter has now been subdivided into three chapters: nasopharynx, HR-HPV-associated oropharyngeal cancers, and hypopharynx and non-HR-HPV-associated oropharyngeal cancers

Overexpression of p16 by immunohistochemistry defines HPV-positivity in the AJCC 8 ^th edition. p16 is a robust surrogate biomarker for HPV positivity because it detects p16 cyclin-dependent kinase inhibitor, which is upregulated when HPV-associated oncoproteins degrade p53 and pRB. Typically, p16 immunohistochemical stains on head and neck tumors demonstrate either diffuse and strong staining or are entirely negative. Optimal cut-off for p16 overexpression as a surrogate biomarker for HR-HPV presence is ≥+2/+3 nuclear staining intensity with ≥ 75% distribution. p16 evaluation was chosen by the AJCC over direct detection of HPV owing to its simplicity and resultant greater availability worldwide, cheaper cost, and improved survival stratification. For ease, we will refer to HR-HPV-associated oropharyngeal cancers as p16-positive oropharyngeal cancers and non–HR-HPV-associated oropharyngeal cancers as p16-negative oropharyngeal cancers.