Cancer of the Oropharynx

David M. Neskey

Katherine A. Hutcheson

Michael E. Kupferman

Nearly 10,000 cases of cancer of the oropharynx are diagnosed each year in the United States.¹ Previously, these cancers had a strong association with chronic alcohol and tobacco use, but over the past decade, the increasing incidence of the human papillomavirus (HPV) has been identified as a major etiologic agent of the oropharynx cancer.¹^,² HPV-associated squamous cell carcinoma (SCC) is now the predominant histologic type found in the oropharynx although non-HPV-associated SCC subtypes and minor salivary gland cancers are seen but less frequently.

Cancer of the oropharynx represents a diagnostic and therapeutic challenge because of the key role that the anatomic region plays in the normal function of speech, swallowing, and breathing, which requires an individualized, multidisciplinary approach for management. Head and neck surgeons, radiation and medical oncologists, speech pathologists, and dental oncologists must work in concert toward the goals of eradicating the disease, preserving function, and, when needed, functionally rehabilitating these patients after treatment. Because these cancers are frequently deeply invasive and/or present with extensive regional lymph node metastases, local-regional control is the primary therapeutic goal. Patients with HPV-associated SCC have improved survival rates compared to their non-HPV-associated counterparts, for whom overall survival rates have not improved dramatically over the past 30 years.³^,⁴ Advances in both radiation therapy (RT) with the advent of intensity-modulated RT and surgical approaches with laser microsurgery and robotic surgery will hopefully continue to improve survival rates while decreasing the shortand long-term morbidity. Finally, as prognostic and predictive biomarkers become validated in clinical practice, the management of oropharyngeal cancers will hopefully become more individualized.

ANATOMY

Boundaries

The oropharynx is a three-dimensional structure bounded anteriorly by the anterior tonsillar pillars (the palatoglossus muscle), the circumvallate papillae (sulcus terminales), and the junction of the hard and soft palate. Posterior and lateral boundaries are formed by the muscular pharyngeal wall (superior and middle constrictors). The superior extent is the level of the soft palate (some define this as the level of the hard palate). The inferior extent is to the vallecula at the level of the hyoid. The oropharynx is further subdivided into five areas, which include the lateral pharyngeal walls, tonsillar regions, posterior wall, base of the tongue, and soft palate. Additionally, the pharynx consists of six major muscles, the superior pharyngeal constrictor, middle pharyngeal constrictor, inferior pharyngeal constrictor, stylopharyngeus, salpingopharyngeus, and palatopharyngeus.

Cancer arising in the oropharynx can extend laterally or posteriorly to involve the parapharyngeal or retropharyngeal spaces, respectively. Lateral extension through the superior constrictor muscle can involve any of the structures of the poststyloid compartment of the parapharyngeal space including the carotid artery, jugular vein, cranial nerves IX through XII, and the sympathetic chain. The posterior pharyngeal wall begins at the Passavant ridge of the superior constrictor. The layers of the posterior pharyngeal wall are critical to the understanding of the spread of cancer in this area and include mucosa, submucosa, superior constrictor, pharyngobasilar fascia, and prevertebral fascia. The pharyngobasilar fascia is a natural barrier to the spread of cancer and is separated from the prevertebral fascia by areolar tissue. Posterior extension of cancer through the muscles and into the pharyngobasilar fascia, but not the prevertebral fascia, can still allow a complete surgical resection with clear margins. In contrast, once the prevertebral fascia is involved, or is fixed to the vertebral bodies, the cancer is no longer considered to be resectable (Fig. 14.1A-C).

The base of the tongue extends from the circumvallate papillae to the vallecula at the base of the epiglottis and encompasses the glossoepiglottic and pharyngoepiglottic folds. Superiorly and laterally, the base of the tongue extends to the glossopalatine sulcus and the glossopharyngeal folds inferiorly and laterally.

Innervation

Most of the sensory innervation of the pharynx is derived from the glossopharyngeal nerve (cranial nerve IX), specifically through its pharyngeal and tonsillar branches. The pharyngeal branch arises prior to the glossopharyngeal nerve traveling intimately with the stylopharyngeus muscle. The pharyngeal branch then merges with the pharyngeal branch of the vagus nerve (cranial nerve X), which then proceeds to the pharyngeal plexus located within the external fascia of the pharynx. Although the pharyngeal branch provides most of the sensory innervation, the tonsillar branch of the glossopharyngeal nerve directly supplies the oropharyngeal isthmus as it communicates with the lesser palatine nerve (from cranial nerve V2). The soft palate receives its innervation from the lesser palatine branch of the maxillary nerve. The six major muscles of the pharynx all derive motor input from pharyngeal and superior laryngeal branches of the vagus nerve (cranial nerve X) through the pharyngeal plexus, except the stylopharyngeus. Instead, the stylopharyngeus muscle derives motor innervation from the glossopharyngeal nerve (cranial nerve IX) from fibers of the nucleus ambiguus (Fig. 14.2).

Figure 14.1. A-C: Anatomic boundaries of the oropharynx.

Figure 14.1. (Continued)

Figure 14.2. Innervation of the oropharynx.

Vasculature

The pharynx receives its blood supply from several sources. The superior aspect of the pharynx receives blood from the pharyngeal branch of the ascending pharyngeal artery and descending branches of the lesser palatine arteries. The inferior aspect of the pharynx receives blood supply from the inferior thyroid artery and superior thyroid artery. The rest of the pharynx receives blood from the ascending palatine and tonsillar branches of the facial artery as well as from the maxillary artery. The internal carotid artery, which is an essential surgical landmark, lies deep to the superior constrictor muscles and medial to the medial pterygoid muscle. It is generally covered in adipose tissue within the prevertebral fascia⁵ (Fig. 14.3).

Lymphatics

The lymphatic drainage of the oropharynx varies greatly across the different subsites, but the two lymph node basins most frequently involved are the internal jugular nodes and the retropharyngeal nodes. The base of the tongue has both superficial and deep lymphatic networks that are bilateral in up to 30% of patients. The primary lymph nodes involved in primary cancer of the base of the tongue are levels II-IV. The tonsil drains to the lateral retropharyngeal lymph nodes and ipsilateral level II-III nodes. The soft palate has three distinct drainage systems, anterior, middle, and posterior. The anterior system drains primarily the hard palate and the anterior aspect of soft palate and involves the level I lymph nodes. The middle system can drain bilaterally, most commonly to level II at the
posterior belly of the digastric. The posterior system can also drain bilaterally to the retropharyngeal nodes via penetration of the lymphatics through the superior constrictor muscles.⁶

Figure 14.3. Vascular supply of the oropharynx.

EPIDEMIOLOGY, RISK FACTORS, AND PREVENTION

SCC of the oropharynx, like tumors from other head and neck subsites, has been traditionally associated with tobacco and alcohol consumption. In contrast to nonoropharyngeal cancers, the incidence of oropharyngeal squamous cell carcinoma (OPSCC) has increased in recent decades, specifically among younger age groups.⁷^,⁸^,⁹^,¹⁰^,¹¹ This decline in incidence of nonoropharyngeal cancers may be attributed to reductions in tobacco use in the United States, whereas the rising incidence of oropharyngeal cancers is due to a higher incidence of infection with HPV.¹^,¹²

The prevalence of HPV in OPSCC in the United States has steadily increased from <20% in the 1980s to over 70% in 2004, with palatine and lingual tonsils most frequently involved.¹^,³ With a conservative estimate that 70% of OPSCC are HPV positive, it is projected that over 11,300 new cases will be diagnosed in the United States in 2020, and by 2030, 47% of all HNSCC will originate from the oropharynx¹ (Fig. 14.4). This increase in OPSCC has also been observed in other countries, specifically Canada, Slovakia, the Scandinavian countries, and Greece.¹³^,¹⁴^,¹⁵^,¹⁶^,¹⁷ The risk factors associated with HPV-associated OPSCC are distinct from HPV-negative tumors and include oral sexual behaviors and marijuana use, whereas HPV-negative tumors are associated with poor dental hygiene and tobacco and alcohol use.¹⁸ Furthermore, a dose-response relationship has been identified between the risk of developing HPV-positive OPSCC with number of oral sex partners and joint years of marijuana use.¹⁸

HPVs are DNA viruses with a unique affinity for human epithelia, and HPV-associated cancers typically arise from the palatine or lingual tonsillar crypts de novo without clear evidence of epithelial dysplasia. Over 120 different HPV types
have been isolated, with low-risk types (e.g., HPV 6, 11) inducing benign hyperproliferation of the epithelium, leading to lesions such as papillomas and warts. High-risk types (e.g., HPV 16, 18, 31, 33, 35) are defined by epidemiologic associations with cervical cancer.¹⁹ The prototypical oncogenic types 16 and 18 account for over 90% of HPV-related OPSCC and are capable of malignant transformation of primary human keratinocytes from either genital or upper respiratory tract epithelia.²⁰ This transforming potential is attributed to two HPV oncoproteins, E6 and E7, that inactivate two human tumor-suppressor proteins, p53 and pRb, respectively. These viral oncoproteins lead to transformation through the stimulation of cellular proliferation, delay of cellular differentiation, increase in the frequency of spontaneous and mutagen-induced mutations, and promotion of focal and broad chromosomal instability in transfected cell lines²¹ (Fig. 14.5). Furthermore, in order to maintain a malignant phenotype, a transcriptionally active viral genome appears to be necessary.²²^,²³^,²⁴^,²⁵

Figure 14.4. A: Incidence rates for oropharyngeal cancer (overall), HPV-positive oropharyngeal cancer, and HPV-negative oropharyngeal cancer. B: Projected annual number of patients with oropharyngeal, oral cavity, laryngeal, and other pharynx cancers through the year 2030. Observed incidence rates during 1973 to 2007 from nine registries within the Surveillance, Epidemiology, and End Results (SEER) program were used in age-period-cohort models to project expected incidence through the year 2030. (Adapted from Mehanna H, et al. Prevalence of human papillomavirus in oropharyngeal and nonoropharyngeal head and neck cancer-systematic review and meta-analysis of trends by time and region. Head Neck. 2013;35(5):747-755. http://dx.doi.org/10.1002/hed.22015. PubMed PMID: 22267298, with permission; and data from Chaturvedi, AK, et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol. 2011;29(32):4294-4301.)

In the normal viral life cycle, the genome replicates as episomally.²⁶ In cervical lesions, the HPV genome is consistently retained in the episomal state in early dysplasia and low-grade lesions, but integration of the viral genome into the host chromosome is associated with high-grade lesions and the majority of HPV-associated cervical carcinomas.²⁷^,²⁸^,²⁹ This integration appears to be a direct consequence of host chromosomal instability and is an important molecular event in the progression from high-grade lesions to invasive carcinoma.³⁰ A possible explanation for this disease progression is the dysregulation of the viral oncogenes following integration due to complete or partial loss of E2 open reading frame (ORF).³⁰ This hypothesis is supported by the finding that E6 and E7 confer a much stronger transforming capacity in primary cells following integration compared to episomal transcripts.³¹ The HPV integration sites are randomly distributed throughout the host genome with a clear preference for genomic fragile sites. Viral integration is a consequence of an overall destabilization process of the chromosomal integrity in replicating epithelial cells that express the viral E6 and E7 genes. Therefore, alterations in the viral genome secondary to integration and the impact of the host cellular sequences on transcriptional regulation of the viral genes appear to be more important than cellular alterations due to the HPV integration²⁶^,³⁰ (Fig. 14.6).

The increasing incidence of HPV-positive OPSCC raises important public health considerations, which utilizes health promotion and primary prevention strategies aimed to decrease the incidence of this disease. The prevalence of oral HPV-16 infection is 1% in the United States and has been associated with a 50-fold increased risk for HPV-positive OPSCC.¹⁸^,³² In the primary care setting, risk factor modification including reduction in high-risk sexual behavior, decreased oral HPV infection, and smoking cessation should be discussed with patients.

Figure 14.5. The mechanisms of HPV oncogenes E6 and E7 in cancer development.

Because HPV-positive OPSCC is related to only a few high-risk HPV subtypes, the potential exists for prevention of this disease through vaccination targeting those subtypes.³²^,³³ Unfortunately, vaccination is effective only prior to infection, because it induces neutralizing antibodies that prevent virion entry but does not halt the progression of existing lesions; therefore, vaccination must occur at a young age.³⁴^,³⁵ The two vaccines (HPV bivalent29 and quadrivalent30 vaccines) approved by the U.S. Food and Drug Administration (FDA) prevent persistent cervical HPV-16 infection.³⁵ The bivalent vaccine is indicated for the prevention of cervical cancer in women, whereas the quadrivalent vaccine has an additional approval for the prevention of genital warts and genital cancers in both genders up to 26 years of age. The Advisory Committee on Immunization Practices first recommended in 2007 that girls 11 to 12 years of age be vaccinated with the quadrivalent HPV vaccine. The recommendation was updated in 2011 that boys aged 11 or 12 years should also be vaccinated with three shots.³⁶ Females 13 to 26 years of age and males 13 to 21 years of age who were not previously vaccinated are recommended to be vaccinated. Because there is no screening strategy for OPSCC, vaccination may have higher impact in OPSCC than in cervical cancer, given that the incidence is estimated to surpass that of cervical cancer by 2020.¹ Parents of children of both sexes should be informed that vaccination is available, and, although not approved for this indication, it may reduce the risk of other HPV-related cancers, including OPSCC.

PATHOLOGY

As mentioned previously, the oropharynx is divided into subsites that are lined with distinct epithelial types. The posterior pharyngeal wall, which begins at Passavant ridge, transitions from ciliated respiratory epithelium of the nasopharynx to nonkeratinizing stratified squamous epithelium of the oropharynx. The lymphoepithelium of Waldeyer ring is formed by the fusion of the overlying stratified squamous epithelium that extends into the deep tonsillar crypts within the underlying lymphoid tissue.³⁷ Minor salivary glands are located throughout the submucosa of the oropharynx.

SCC accounts for over 90% of the malignant neoplasms in the head and neck. Although SCC of the head and neck has classically been considered a homogeneous disease, recent epidemiologic trends and molecular profiling have identified distinct subtypes.¹⁸^,³⁸ With the emergence of HPV-associated OPSCC, the typical differentiated keratinizing and nonkeratinizing SCC of the head and neck represents an increasingly smaller proportion of neoplasms in the oropharynx. Tumors of this histology tend to arise in older patients with a history of tobacco and alcohol abuse.⁴

Non-HPV-Related Squamous Cell Carcinoma

Keratinizing SCC tends to be fungating and ulcerative with limited submucosal spread but infiltrating margins. The presence of intracellular and extracellular keratin is common, and the cells are large and have the characteristic intracellular bridges.³⁶ Nonkeratinizing SCCs occur less frequently than do their keratinizing counterparts and grow in broad connecting bands resembling a plexus with cells that contain prominent nucleoli.³⁶

Basaloid SCC is a rare but aggressive subtype of SCC that primarily arises in the base of the tongue. This cancer has a propensity for submucosal spread with central ulceration and is composed of tightly packed moderately pleomorphic cells that form cords and nests. Patients typically present with latestage disease including regional and distant metastases.³⁶

Spindle cell carcinoma is a fusion between classic SCC with spindle cells and can be referred to as sarcomatoid carcinoma.
The spindle cell component tends to form the bulk of the tumor with the SCC being restricted to the stalk or base. These cancers will stain for both epithelial markers including keratin and mesenchymal markers including vimentin.³⁹

Figure 14.6. Significance of HR-HPV integration events detected in cervical carcinomas. The majority of integrants that derive from insertion of HR-HPV episomes (HR-HPV_EPI) into the host genome are detected at low copy number and retain at least the E6 and E7 oncogenes together with the viral upstream regulatory region (URR). Integrant copy number is often increased through amplification of viral and flanking host DNA. Typical integrants also have complete or partial disruption of the ORF for E2, the viral gene that regulates viral replication and which, by binding sites in the URR, can inhibit expression from integrated virus. Disruption of the viral genome also dissociates viral early (E) gene transcription from the viral early polyadenylation signal, leading to use of host poly(A) signals and transcription of virus-host fusion transcripts with a longer half-life. These events lead to increased levels of E6 and E7 proteins, which, together with loss of additional inhibitory effects of E2, result in cellular immortalization, deregulated proliferation, and increased genomic instability. More rarely, concatemeric integrants are observed, where viral copies (including intact E2) are arranged in a head-to-tail fashion with partially deleted copies at the 5 and 3 ends. Note that the dashed line in the figure represents transcription from the early promoter of HR-HPVEPI (P97 in HPV16). (Adapted from Pett M, Coleman N. Integration of high-risk human papillomavirus: a key event in cervical carcinogenesis? J Pathol. 2007;212(4):356-367, with permission.)

Lymphoepithelial carcinoma is histologically identical to undifferentiated nasopharyngeal carcinoma (WHO III). Cancer cells are typically surrounded by lymphocytes and have large vesicled nuclei that are positive for cytokeratin. Like NPC, these cancers tend to arise in younger patients, are not associated with alcohol or tobacco, and are radiosensitive.⁴⁰

HPV-Related OPSCC

The pathologic features of HPV-related SCC of the oropharynx are distinct from those of the keratinizing differentiated SCC that arises from the other head and neck sites. The unique histologic features include lesions that arise from the tonsillar crypts without associated dysplasia of the epithelial surface. Additionally, these cancers exhibit lobular growth and are infiltrated with lymphocytes. Finally, the cells lack significant keratinization and demonstrate a prominent “basaloid” morphology.⁴¹ There are two microscopic features of HPV-related oropharyngeal cancers that are frequently misunderstood. First, these cancers are frequently described as poorly differentiated based on immature appearance of the cells, when in fact these cells closely resemble the reticulated epithelium of the tonsillar crypts and are actually highly differentiated.⁴² Second, the “basaloid” descriptor can be misleading and associate these cancers with aggressive basaloid SCC subtype. Although these two SCCs look similar morphologically, the detection of HPV results in significantly improved survival outcomes relative to the HPV-negative basaloid SCC.⁴³

Minor Salivary Gland

Tumors of the minor salivary glands represent fewer than 10% of neoplasms in the oropharynx, but unlike tumors of the major salivary glands, the majority of tumors are malignant.⁴⁴^,⁴⁵ The
majority of minor salivary gland tumors arise in the base of the tongue, followed by the soft palate and palatine tonsil.⁴⁶ The histologic heterogeneity in the minor salivary glands mirrors that of the major salivary glands, with adenoid cystic and mucoepidermoid carcinomas being the most frequent. There are conflicting data as to which neoplasm is actually the most frequent, but a recent series that focused on minor salivary gland malignancies of the oropharynx identified mucoepidermoid carcinomas as the most frequent, followed by adenoid cystic carcinoma, polymorphous low-grade adenocarcinoma, and carcinoma ex-pleomorphic adenoma.⁴⁶

DIAGNOSIS

History

A complete history including review of systems, personal and family history of cancer, social history, and sexual history needs to be documented. As mentioned previously, the risk factors associated with HPV-positive tumors are distinct from HPV-negative tumors. Marijuana use of >1 cigarette per day for at least 5 years and >11 vaginal sex partners or 6 oral sex partners are most closely associated with HPV-positive OPSCC.¹⁸ In contrast, the risk of developing HPV-negative OPSCC is associated with being a current smoker, a >20 pack-year history of tobacco smoking, and >14 drinks per week for 50 years.¹⁸ Because of these differences in risk factor profiles, a thorough history needs to be gathered because of the HPV status of the cancer at presentation.

Figure 14.7. Examination of the oropharynx through direct transoral visualization (A) or flexible nasopharyngoscopy (B-D). Normal appearance of the base of the tongue and vallecula (B). Exophytic neoplasm along the glossopharyngeal sulcus (C). Small exophytic lesion of the vallecula (D).

The presenting symptoms also differ between HPV-positive and HPV-negative tumors. Patients with HPV-positive tumors typically have smaller primary cancers and therefore rarely have local symptoms at presentation but will often have a painless mass in the neck secondary to regional metastases.⁴⁷ In contrast, patients with HPV-negative cancers tend to have a greater disease burden at the primary site, which results in more local symptoms of pain, otalgia, and dysphagia.

Physical Examination

A complete examination of the head and neck should be performed on all patients. Systematic inspection of all the mucosal surfaces of the upper aerodigestive tract is necessary because of the field cancerization phenomenon that can lead to synchronous primaries, particularly in the patient with non-HPV-associated cancer.⁴⁸ Visual inspection of the base of the tongue and larynx is greatly facilitated with a fiberoptic nasopharyngoscope (Fig. 14.7A-D). In addition to inspection of the mucosal surfaces, the tonsils and base of the tongue must be palpated to assess the extent of the tumor and for
any submucosal spread. Moreover, the extent of the lesion into the deep tissues of the base of the tongue, vallecula, and glossopharyngeal sulcus is often only evident upon palpation. Assessment of the mandible range of motion and a thorough examination of the cranial nerves also must be performed, with an emphasis on sensation of the lower face and tongue, along with mobility of the tongue and palate. Cranial nerve deficits or the presence of trismus implies local invasion into the mandible or masticator spaces. All levels of the neck must be evaluated bilaterally, given the rich lymphatic network that drains the oropharynx and the high incidence of metastasis to the cervical lymph nodes.

Diagnostic Imaging

Computed tomography (CT) and magnetic resonance imaging (MRI) are helpful in determining the extent of disease at the primary site or regionally. They are primarily indicated in the assessment of advanced-stage cancers where there is concern for involvement of the mandible, parapharyngeal space, prevertebral fascia, cervical nodes, or retropharyngeal nodes. CT scans are better able to evaluate bony structures and cervical lymphadenopathy, whereas MRI is better at evaluating soft tissue, such as the base of the tongue, parapharyngeal space, or prevertebral fascia.
Chest radiograph is useful as a screening for metastasis to the lungs, second primary cancers, and chronic changes associated with the use of tobacco. If a patient presents with significant lymphadenopathy that is in the inferior aspect of the neck (levels IV or VB) or bilateral in nature, a CT of the chest to detect lung metastases should be considered.
A panorex is a study complementary to the CT scan for the detection of mandibular involvement, and it is also critical in the assessment of the dentition prior to radiation therapy.
Positron emission tomography (PET) in conjunction with a contrast-enhanced CT of the neck can provide accurate anatomic details along with the biologic function about the primary tumor and regional disease. Because HPV-associated SCC frequently presents with smaller primary cancers and the nodal metastases are commonly cystic in nature, the additional functional characteristics provided by the 18F-FDG PET can improve the initial staging of these patients.³^,⁴⁹^,⁵⁰ Furthermore, although an increased frequency of distant metastases is not related to HPV status, HPV-associated OPSCC tends to disseminate to multiple organs that are not typically involved in non-HPV-associated metastatic HNSCC.⁵¹ These metastases also can manifest later in the course of the disease between 3 and 5 years after completion of treatment.⁵¹ Due to this atypical pattern of disease spread, initial and surveillance imaging needs to assess distant sites of disease. The benefit of PET/CT relative to a contrast-enhanced CT in the assessment of treatment response is still not clear. One of the challenges is the timing of the posttherapy PET/CT. The optimum timing after chemotherapy and radiation therapy is not known, but an interval of 12 weeks has generally been recommended to allow for a reduction in the radiation-induced inflammation and therefore improve the accuracy of the test.⁵²

Laboratory evaluation of patients with cancer of the oropharynx includes a complete blood count, electrolytes, creatinine, BUN, and liver function tests.

Staging Endoscopy and Biopsy

Patients with primary epithelial cancers of the upper aerodigestive tract should undergo examination under anesthesia independent of the presenting T stage. Direct visualization and palpation of the tumor improve the assessment of submucosal spread and invasion of surrounding structures, especially in patients presenting with trismus. A thorough examination using direct laryngoscopy for a synchronous second primary cancer is essential, as these lesions can occur in 8% to 12% of patients with history of tobacco use.⁴⁸^,⁵³ Bronchoscopy can also be performed to evaluate for small distant metastases or second primary cancers of the lung, which have been reported to occur in 2% HNSCC patients independent of stage.⁵⁴ The findings from the examination under anesthesia and endoscopy are then used to calculate clinical staging of the primary site.

Approximately 2% to 9% of patients who have cancer of the oropharynx will initially present with cervical lymphadenopathy with an unknown primary.⁵⁵ The most common sites of primary lesions are the tonsillar fossa and base of tongue, which account for 82% of cases.⁵⁶ Panendoscopy is crucial for these patients and tonsillectomy is recommended if the primary cancer is not identified as up to 25% of unknown primaries are located in this site. Bilateral tonsillectomy is merited in these cases because of a 10% rate of contralateral spread from occult tonsil lesions.⁵⁷^,⁵⁸ More recently, transoral robotic surgery (TORS) has been used to identify the unknown primary site in the tongue base in patients who have undergone a panendoscopy and tonsillectomy.⁵⁹ The most recent AJCC staging guidelines for SCC of the oropharynx use only tumor size, lymph node involvement, and the presence of distant metastases as predictors of overall survival (Table 14.1). Future alterations to the AJCC system will likely include HPV status as a major component of patient staging.

Laboratory Diagnosis of HPV-Related Tumors

Because the HPV has recently emerged as an important etiological factor in the increasing incidence of oropharyngeal cancer, and as a highly relevant biomarker of treatment outcomes for cancer of the oropharynx, a systematic method of detection is essential. The ideal diagnostic detection methods will either localize the genome of high-risk HPV genome to tumor cell nuclei or demonstrate the expression of viral oncogenes, E6 or E7.⁶⁰ The most commonly used methods to achieve these aims are p16 immunohistochemistry and in situ hybridization.⁶¹ p16 immunohistochemistry has emerged as a reliable surrogate marker of HPV-induced neoplasia of oropharynx. In HPV-positive oropharyngeal carcinomas, transcription of the viral oncoprotein E7 is known to functionally inactivate the retinoblastoma (Rb) gene product. Disruption of this pathway leads to an upregulation of p16 expression that can be detected by immunohistochemistry.⁴² In situ hybridization probes are type specific, and therefore multiple probes are necessary to test a complete tumor genotype. Because 90% to 95% of cancers of the head and neck are related to HPV 16 and to a lesser extent HPV 31, 33, 35, the false negative rate of ISH is low.⁶² Direct comparison of p16 immunohistochemical staining and HPV-16 ISH for large numbers of HNSCCs reveals a 24% discordance rate. The discrepancies consistently involve cancers that are negative
by HPV16 ISH but p16 positive by immunohistochemistry. About 45% of these cases can be attributed to the presence of some other (non-16) HPV type, as confirmed by wide spectrum ISH. The remaining discrepancies are probably due to false-positive staining of p16, which can be seen in basaloid carcinomas that are not related to HPV infection.⁶² To optimize HPV detection, a combination of p16 staining with ISH is the most effective. Because the sensitivity of p16 IHC approaches 100%, this is a reasonable first-line test to confidently eliminate those cases that are HPV negative. HPV16 ISH can then be run as a second-line assay for the p16-positive cases, and given a specificity of nearly 100%, the number of false positives from p16 staining alone will be reduced. The combination of these two assays identifies a subset of cancers that require a more rigorous analysis for non-HPV 16 oncogenic types. This third-line assay can either be consensus ISH probe set or PCR for the detection of transcriptionally active virus. This algorithm accurately detects HPV in the majority of cases, and although some tumors may require a more extended analysis, the overall expense is reduced because these cases are preselected.

Table 14.1 AJCC Staging for Squamous Cell Carcinoma of the Oropharynx

Tumor (T) Stage
T1	≤2 cm
T2	2-4 cm
T3	>4 cm or extension to lingual surface of epiglottis
T4a	Invades larynx, extrinsic muscles of tongue, medial pterygoid, hard palate, or mandible
T4b	Invades lateral pterygoid muscle, pterygoid plates, lateral nasopharynx, skull base, or encases carotid
Lymph Node (N) Stage
N0	No regional lymph node metastasis
N1	Metastasis in a single ipsilateral lymph node, ≤3 cm in greatest diameter
N2a	Metastasis in a single ipsilateral lymph node, >3 cm in greatest diameter
N2b	Metastases in multiple ipsilateral lymph nodes, none >6 cm in greatest diameter
N2c	Metastases in bilateral or contralateral lymph nodes, none >6 cm in greatest diameter
N3	Metastasis in a lymph node >6 cm in greatest diameter
Overall Stage
Stage	T	N	M
0	Tis	N0	M0
I	T1	N0	M0
II	T2	N0	M0
III	T3	N0	M0
	T1	N1	M0
	T2	N1	M0
	T3	N1	M0
IVA	T4a	N0-N2	M0
IVA	T1-T3	N2	M0
IVB	T4b	Any N	M0
IVB	Any T	N3	M0
IVC	Any T	Any N	M1
From Weinstein GS, et al. Transoral robotic surgery for advanced oropharyngeal carcinoma. Arch Otolaryngol Head Neck Surg. 2010;136(11):1079-1085. Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer Science and Business Media LLC, www.springer.com.