Emergence of a Novel Staging System for Oropharyngeal Squamous Cell Carcinoma Based on HPV Status

The staging of oropharyngeal squamous cell carcinoma has undergone key changes in the eighth edition of the American Joint Committee on Cancer Staging Manual, set to take effect January 1, 2018. The most significant change relates to the development of a novel staging system for human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinomas, distinct from that for non–HPV-associated squamous cell carcinomas of the oropharynx. We describe the revised staging parameters and the rationale in support of the changes.

Staging is an important aspect of cancer care at both the individual and the population level. At the individual level, careful assessment of the anatomic and nonanatomic aspects of the disease and of the individual harboring the cancer are crucial to understanding prognosis and to making appropriate treatment recommendations. In addition, stratification of populations based on stage promotes innovations in care through clinical trials, proper comparisons of like populations between institutions and nations, and a common language for cancer registrars to use to appropriately collect and catalog data. To achieve these broad goals, staging systems are based on anatomic extent of disease at the primary site, in regional lymph nodes, and in distant organs, according to the Tumor, Node, Metastasis (TNM) concept developed around the middle of the last century by Denoix.[1]

Over time, as per the initial plan of the American Joint Committee on Cancer (AJCC), at appropriate intervals, the AJCC Cancer Staging Manual has required updates and improvements as new knowledge has become available.[2] Careful and thoughtful merging of the Union for International Cancer Control (UICC) and AJCC manuals was eventually accomplished, bringing international consistency and facilitating collaboration. The changes we will describe represent a careful merging of the ideas and expertise of members of head and neck task forces from the AJCC and the UICC. Thus, while from here on we will refer to the AJCC Cancer Staging Manual, these changes are also largely reflected in the UICC publication. Ever mindful of the need to balance cutting-edge improvements with consistency over time and with sensitivity to resource availability, new editions of the AJCC Cancer Staging Manual have been produced at regular intervals. The eighth edition, published in the late fall of 2016, continued this tradition.[3] Because of the need to update all elements of our complex modern healthcare system-such as electronic medical records, organizational guidelines, and cancer registries-and in order to allow healthcare providers to adapt and incorporate all of the novel improvements, the new staging system will take effect January 1, 2018. This article is designed to provide oncologists with insights into the key changes and novel staging systems in the eighth edition of the AJCC Manual, which have been developed in response to emerging knowledge about the clinical behavior of human papillomavirus (HPV)-associated and non–HPV-associated oropharyngeal squamous cell carcinoma (OPSCC).

Understanding the statistical parameters that inform the definition of cancer stages is critical to accurate and informative staging. The first consideration is to make sure that each stage contains similar types of disease and predicts similar behavior. In statistical parlance, this is known as “hazard consistency.” Ensuring that each stage has behavior that is distinct from that of the stage above and the stage below is known as “hazard discrimination.” “Numerical balance” implies that a relatively similar number of patients are included in each stage. Finally, and most obviously, “predictive power” is essential for clinicians and others to be able to make optimal use of a staging system.

Evolving Etiology and Clinical Behavior of OPSCC: Rationale for Stage Modification

Traditionally, OPSCC has been associated with risk factors such as tobacco and alcohol use. However, HPV-associated OPSCC has emerged as a novel disease, prompting the need for a staging system that reflects and differentiates the favorable prognosis and the unique clinical behavior of patients affected by this entity. In contrast to non–HPV-associated OPSCC, patients affected with HPV-associated OPSCC are typically younger, have fewer comorbidities, and have limited or no exposure to tobacco.[4,5] Additionally, numerous investigations have shown more favorable prognostic outcomes for HPV-associated OPSCC compared with non–HPV-associated disease.[6] Data from the Radiation Therapy Oncology Group 0129 trial show that the 3-year overall survival rate for HPV-associated OPSCC was 82.4%, in contrast to 57.1% for the non–HPV-associated group. A similar advantage in progression-free survival was noted between the two groups based on HPV association (73.7% vs 43.4%, respectively).[6]

The underlying mechanisms for the improved survival are not entirely clear, but are thought to be related to younger age, superior baseline health, and lower mutation burden. This is important because it means that counseling for patients with HPV-associated OPSCC may be substantially different from that for patients with non–HPV-associated OPSCC. For example, improved survival outcomes for patients in the former group imply that many of these patients will have prolonged survivorship, and may thus experience long-term treatment-related effects, resulting in progressive functional loss that manifests many years later. These differences meant that the seventh edition of the AJCC staging system for OPSCC no longer provided significant hazard consistency or discrimination for HPV-associated tumors.[7] This led to incongruence in assigned stage and subsequent outcome, resulting in an inappropriately high number of patients classified as stage IV, thus presenting unique challenges with regard to advising, counseling, and managing these patients. The eighth edition of the AJCC staging system[3] recognizes HPV-associated OPSCC as a disease distinct from the non–HPV-associated variant, and it provides a unique classification for nodal disease (N category) and more appropriate stage groupings in HPV-associated disease.[8]

Rules for Classification

OPSCC: Anatomical considerations

The oropharynx encompasses the mucosal surfaces posterior to the circumvallate papilla of the tongue, the anterior fascial arches of the tonsil, and the junction of the hard and soft palate, inferior to a posterior plane extending from the hard palate and superior to a plane corresponding to the superior surface of the hyoid bone. Malignancies arising in the squamous lining of the base of the tongue, palatine tonsils, anterior and posterior tonsillar pillars, glossotonsillar sulcus, inferior surface of the soft palate and uvula, and the lateral and posterior wall of the pharynx qualify as OPSCC.[3] The drainage pattern from these sites determines the most common location of regional nodal metastases to level II and III cervical lymph nodes. Distant metastases usually involve the lungs, although bone, liver, and other soft-tissue sites may also be involved.

History and physical examination

Patients with suspected OPSCC should be asked about pertinent risk factors, including tobacco and alcohol use. In addition to its negative prognostic association in non–HPV-associated OPSCC, tobacco use (especially more than a 10–pack-year history of cigarette smoking) has been linked to a decline in survival in patients with HPV-associated OPSCC.[9] Clinicians should note other comorbid conditions, history of depression,[10] nutritional impairment, and other indications of frailty that may contribute to adverse patient outcomes.

Physical examination of the oropharynx should focus on meticulous inspection of mucosal surfaces, and should include the use of magnified flexible fiberoptic endoscopy in the clinic, when applicable. Palpation of oropharyngeal structures, when tolerated, should also be performed. Detailed assessment of cranial nerve function should be documented. Cervical nodal assessment should also be performed, including inspection and palpation. When present, suspicious nodes should be assessed for size, number, laterality, mobility, consistency, and adherence to underlying soft tissue or overlying skin. Findings suggestive of immobility of an enlarged lymph node, infiltration of adjoining skin and soft tissue, or cranial neuropathy should alert the clinician to the possibility of extranodal extension. This is very relevant to the staging of non–HPV-associated oropharyngeal cancers, as it will result in a higher N classification. However, the role of extranodal extension in HPV-associated oropharyngeal cancers is not as clear, and while it is prudent to note it in the staging evaluation, it will not change the N designation. When required, examination under anesthesia may supplement physical examination findings and may facilitate biopsy of suspicious mucosal lesions, particularly when cytology or tissue biopsy from target areas obtained in the clinic fails to establish the suspected diagnosis. In patients in whom a mucosal primary site is not clearly apparent, clinicians should consider obtaining positron emission tomography (PET) fused with cross-sectional CT imaging prior to proceeding with biopsy under anesthesia to avoid false-positives resulting from surgical trauma.

Radiographic assessment

Contrast-enhanced CT and MRI are the preferred imaging modalities for assessment of anatomical extent of local and regional disease. PET/CT is useful for evaluating distant metastatic sites, particularly in patients with large primary tumors, advanced nodal disease, or involvement of inferior nodal stations (for example, level IV). However, caution must be exercised when using PET/CT for the assessment of local disease, due to concerns that it may overestimate disease burden in some settings. Given available resources, clinicians may opt for CT in lieu of PET/CT for the evaluation of distant metastatic disease. It is critical to recall that in clinical scenarios of uncertainty, the clinician should always choose the lesser T, N, or M category.

Currently available imaging modalities do not reliably predict extranodal extension, although spiculated and ill-defined borders of an enlarged lymph node that is obviously infiltrating into adjacent muscle, soft tissue, or neurovascular structures is strongly suggestive.[11] In non–HPV-associated OPSCC, clinical examination findings remain the only determinant of extranodal extension used in the eighth edition of the AJCC Cancer Staging Manual, and imaging serves to support clinical findings. Importantly, in HPV-associated OPSCC, extranodal extension is not used in staging. Additionally, while patients with HPV-associated OPSCC often present with cystic adenopathy, the appearance of such findings on imaging is not sufficient for determination of HPV status or of subsequent staging (Figure 1).

Determination of HPV Association Is Critical for Appropriate OPSCC Staging and Prognostication

All patients diagnosed with OPSCC, as well as those presenting with pathologic neck adenopathy without clear evidence of a primary site, should undergo determination of HPV association, through cytology or histopathologic assessment of tissue biopsies. Unknown primary metastatic nodes should be evaluated for both HPV and Epstein-Barr virus (EBV). EBV positivity is established by the identification of EBV-encoded RNA using immunohistochemistry (IHC).[12] HPV association can be determined by direct identification of HPV through in situ hybridization (ISH) or polymerase chain reaction (PCR)-or preferably, by identifying HPV’s surrogate marker, p16 (cyclin-dependent kinase inhibitor 2A), via IHC (Figure 2).[13,14]

Importantly, for staging purposes, the stratification of OPSCC into HPV-associated and non–HPV-associated types is dependent on p16 identification alone,[13] and does not require ISH or PCR testing for HPV DNA. This use of p16 for categorization is intended to allow improved global access, since IHC techniques are relatively inexpensive, reproducible, and more readily available. To classify a specimen as p16-positive, several criteria must be met.[15] These include the presence of a nuclear staining pattern, staining intensity that is qualified as 2+ or 3+, and staining of at least 75% of cancer cells examined. Tumors that do not meet all of these criteria should not be staged as HPV-associated (p16-positive) OPSCC. Further, when p16 status is negative, not available, or cannot be determined, clinicians should assign staging based on non–HPV-associated (p16-negative) OPSCC staging schema.[3]

Novel Staging of HPV-Associated (p16-Positive) OPSCC

T classification

The clinical and pathologic classification of primary tumors is similar for both HPV-associated (p16-positive) and non–HPV-associated (p16-negative) OPSCC. However, the classification scheme differs from those for other head and neck sites in several ways. First, the T0 category has been eliminated from the classification systems for non–HPV-associated and EBV-negative malignancies involving other head and neck sites. However, patients with an unknown primary whose regional disease is p16-positive or HPV ISH–positive should be classified as T0 OPSCC. Second, given the absence of a complete, well-defined basement membrane in the crypts of the oropharynx, the category signifying in situ disease (Tis) has been eliminated from the staging system for HPV-associated OPSCC. Finally, due to a lack of hazard discrimination, T4 malignancies in HPV-associated OPSCC are no longer subcategorized into T4a and T4b.[3]

N classification

Distinct clinical and pathologic categorization schemes for nodal involvement have been introduced for patients in this disease group, and the N categories have been reorganized. The clinical nodal classification scheme merges some of the subcategories to improve hazard consistency between N categories, thus stratifying patients into N0, N1, N2, and N3; the subcategories within N2 have been eliminated.

For patients primarily treated with surgical therapy for regional nodal basins, a distinct pathologic N classification has been introduced, since data suggest that an increasing number of involved nodes may be the primary determinant of outcome, instead of other node characteristics, such as size, laterality, or extranodal extension.[7,16] Of patients undergoing neck dissection, those in whom four or fewer pathologic neck nodes are identified are now classified as pN1, and those with five or more involved nodes are classified as pN2. Categories for pN3 have been eliminated to maintain hazard consistency (Table 1).[16]

The clinician may experience dissonance between the clinical and pathologic nodal classification systems. For example, patients with a single node that is greater than 6 cm are classified as N3 in the clinical nodal staging system, but may qualify as pN1 if treated with primary surgical therapy. The availability of additional data specific to the biologic behavior of HPV-associated OPSCC in the context of choice of primary treatment modality may reconcile such instances of discordance over time.

As noted previously, the HPV-associated OPSCC staging system does not use extranodal extension to modify stage determination, since extranodal extension does not appear to have the same detrimental effect on prognosis for patients affected by this disease entity as it does for those with non–HPV-associated OPSCC.[17,18]

Prognostic staging

Patients with HPV-associated OPSCC who present with local and/or regional involvement may be assigned to prognostic stage groups I, II, or III. Many patients who previously would have been classified as stage IV may now be grouped into stage I, II, or III, resulting in greater congruence with expected survival outcomes on account of the substantially different biologic behavior of HPV-associated OPSCC. The lack of a stage IV grouping for patients with even advanced locoregional disease reflects a key difference between the prognosis of this disease and that of non–HPV-associated OPSCC.[7] However, patients with distant metastatic disease on presentation are still assigned to stage IV (Tables 2 and 3).

Modified Staging for Non–HPV-Associated (p16-Negative) OPSCC

Several modifications have been incorporated into the staging of non–HPV-associated (p16-negative) OPSCC. In contrast to the seventh edition of the AJCC Cancer Staging Manual, which classified all tumors of the pharynx in a single chapter, the eighth edition includes three distinct chapters-for staging malignancies involving the nasopharynx, for HPV-associated OPSCC, and for non–HPV-associated OPSCC and hypopharyngeal cancer.[3,19]

T classification

The T categorization of non–HPV-associated OPSCC in the eighth edition of the AJCC Cancer Staging Manual is largely similar to the staging scheme for pharynx cancers in prior versions, with the exception of the removal of the T0 category in HPV-negative cancer. The rationale for retaining most features of prior pharyngeal cancer staging schemes for HPV-negative disease is that, in contrast to situations in which HPV positivity implies an oropharyngeal primary site, and EBV positivity implies a nasopharyngeal primary site, HPV-negative and EBV-negative squamous cell carcinoma identified in an enlarged neck node may have originated from any of a variety of upper aerodigestive tract mucosal sites (including the oral cavity, oropharynx, nasopharynx, hypopharynx, and larynx), or from the skin of the head and neck region, thus making determination of a primary site difficult (Table 4).

N classification and the impact of extranodal extension

Whereas HPV-associated OPSCC now has its own separate N classification, tumors arising in other areas of the upper aerodigestive tract, as well as non–HPV-associated OPSCC, continue to share the same N classification scheme.[3] The most significant change to N classification for non–HPV-associated OPSCC is the incorporation of extranodal extension as a variable. Extranodal extension in non–HPV-associated head and neck SCC portends a worse prognosis independent of other nodal factors.[20-22] However, in HPV-associated OPSCC, as noted earlier, extranodal extension is not similarly linked to adverse prognosis and therefore is not incorporated into nodal staging for that disease, although extranodal extension status will be part of tumor registry data collection.[16-18]

The assessment of the impact of extranodal extension on hazard discrimination between stage groups that led to the inclusion of this factor in the eighth edition AJCC staging relied on an analysis of oral cavity cancer data from the National Cancer Database from 2010 to 2011. Results of this analysis were then validated against a combined patient dataset from two institutions, Memorial Sloan Kettering Cancer Center and Princess Margaret Cancer Centre.[8,23] The rationale for utilizing data from oral cavity cancers to establish the N classification for all non–HPV-associated upper aerodigestive tract malignancies is rooted in the fact that oral cavity carcinoma is generally non–HPV-associated. In addition, there is uniform availability of pathologic staging data for this subsite, since most oral cavity malignancies are primarily managed with surgery.

As in the rules of staging described previously, clinical determination of extranodal extension should be based on findings unequivocally suggestive of fixation of nodes or infiltration into surrounding skin, major nerves, and/or soft tissue. Imaging studies are supportive, but not diagnostic, of extranodal extension for purposes of staging.[11] In situations in which uncertainty over extranodal extension persists, clinicians should opt for the lesser category and assign N class based on extranodal extension–negative status.

When available, pathologic determination of extranodal extension supersedes clinical evaluation. The presence of lymph node metastasis that pushes, but does not invade, the capsule of the lymph node is not sufficient to warrant a designation of extranodal extension–positive. However, once the capsule is breached, a node is considered extranodal extension–positive, irrespective of the extent of the breach. The AJCC recommends categorizing extranodal extension as microscopic (≤ 2 mm of extension from the capsule) or macroscopic (> 2 mm from the capsule or apparent to the naked eye) for data collection purposes, since this may play a role in stage discrimination for future iterations of the staging system.[3]

Prognostic staging

The prognostic stage groupings for non–HPV-associated OPSCC have not changed from the seventh to the eighth edition of the AJCC Cancer Staging Manual. As the new AJCC eighth edition TNM classification starts to be utilized, new data will be incorporated into cancer registries, and these may prompt future reclassification of prognostic stage groupings. At this time, however, the data are insufficient to warrant a change in the stage groupings. Currently, patients with local or locoregional disease can be categorized as stage I, II, III, IVA, or IVB, with stage IVC reserved for patients with distant metastatic disease (Table 5).

Conclusion

The eighth edition of the AJCC Cancer Staging Manual creates distinct staging schema for OPSCC based on HPV association, as determined by p16 positivity or negativity. The new staging guidelines recognize the biologic and epidemiologic diversity in behavior of HPV-associated (p16-positive) and non–HPV-associated (p16-negative) OPSCC. The new stage groups are intended to provide improved hazard consistency, discrimination, and predictive ability that conform to the distinct outcomes expected for patients who suffer from HPV-associated and non–HPV-associated OPSCC.

Financial Disclosure: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

Other Disclaimers:Dr. Lydiatt serves as the vice-chair of the head and neck section of the American Joint Committee on Cancer.

Acknowledgments:We thank Tess Karre, MD (Department of Pathology, Nebraska Methodist Hospital, Omaha, Nebraska) for graciously sharing photomicrographs depicting p16-positive and p16-negative staining patterns. We also acknowledge the dedicated teamwork of the Head and Neck Task Forces of the American Joint Committee on Cancer (led by Jatin P. Shah, MD) and the Union for International Cancer Control (led by Brian O'Sullivan, MB, FRCPC).

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