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.
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. 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. 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. 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).
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. 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 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.
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. 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. Clinicians should note other comorbid conditions, history of depression, 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.
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. 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). 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, 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. 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.
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