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MUSC Otolaryngology - Head & Neck Surgery E-Update                 November 2016 
Colleagues,
Our ENT E-Updates are designed to provide brief, practical, clinical updates in areas where we all struggle in managing our patients. I hope you are finding these newsletters useful. Your feedback or questions about the E-Update articles, your patients, or any other ENT issue are always welcome. Write to us at entupdate@musc.edu - And please forward this E-Update to your colleagues who may also benefit from sharing the latest ENT topics. As always, your support is deeply appreciated.

Yours sincerely,
Paul R. Lambert, M.D.
Professor and Department Chair
Oral Cavity and Oropharyngeal Cancer:
A New Staging System for 2017
Masanari G. Kato, B.S., Terry A. Day, M.D. 
Figure 1. The anatomy of the oral cavity and the oropharynx (used with permission from artist, Lauren Visserman). 
INTRODUCTION

Historically, squamous cell carcinomas of the oral cavity (OCSCC) and oropharynx (OPSCC) have been grouped together as similar diseases with the terms "oral" and "oropharyngeal" used synonymously. The use of these terms interchangeably has since become obsolete, as translational and clinical research has distinguished one from the other in many respects other than just anatomic site, such as by risk factors, patient demographics, etiopathogenesis, and management.
 
These, among other emerging findings, have resulted in evidence that the 7th ed. (2010) American Joint Committee on Cancer (AJCC) staging system may not accurately reflect the differences in stage-related prognosis as a resource to guide treatment. Recently, the AJCC released the 8th ed. of the cancer staging manual, effective January 1st 2017. With this new staging system, notable modifications taken from the latest published research have occurred and are expected to influence current management guidelines.
BACKGROUND

Anatomy
The anatomic separation of the subsites and borders of the oral cavity and oropharynx are often confused, though important to the diagnosis and management of OCSCC and OPSCC. The former begins at the mucocutaneous junction of the lips and extends posteriorly, including the alveolar ridge and gums, the anterior two-thirds of the tongue, floor of the mouth, buccal mucosa, retromolar trigone, and hard palate ( Figure 1).
 
The oropharynx begins superiorly at the junction of the soft and hard palate, and inferiorly at the circumvallate papilla of the tongue. Subsites of the oropharynx include the soft palate, tonsillar pillars, tonsils, base (posterior 1/3) of the tongue, vallecula, and the pharyngeal walls, and is bounded superiorly by the lower surface of the soft palate and inferiorly by the epiglottis (Figure 1). 1
 
Epidemiology
Head and neck cancers (HNC) make up 3% of all cancers in the United States, with a favorable, downward trend in its overall occurrence. 2,3 The rate of OCSCC has paralleled this pattern while OPSCC incidence has been accelerating (Figures 2A, 2B). 2 This observation is due to the surge in human papilloma virus (HPV) associated OPSCCs, approaching 60-80% of all OPSCCs, a subset now often referred to as an "epidemic" in the head and neck community. 4,5 Of note, the incidence of "tongue" cancer is inferred to account for both the oral tongue and base of tongue by both the Surveillance, Epidemiology, and End Results (SEER) database and American Cancer Society, and its rise due to increasing rates of the latter, which is a distinct subsite of the oropharynx (Figure 2A). Thus, Figure 2A shows rising "tongue" cancer, which appears to be primarily a result of the increase in base of tongue as can be appreciated in Figure 2B. Researchers are optimistic that future national databases will separate tongue into the "oral" part of the tongue and separate the "base of tongue" into the oropharynx. Between OCSCC and OPSCC, the American Cancer Society estimates nearly 50,000 new cases will develop, leading to almost 10,000 deaths in the US for 2016 alone. 3
Figure 2. Age-adjusted SEER incidence rates by subsite in the U.S., all races, both sexes from 1975-2013. A. OCSCC declining overall.2 Of note, the incidence of tongue cancer is inferred to account for the oral tongue and base of tongue, and its rise due to increasing rates of the latter, a distinct subsite of the oropharynx B. Rates of OPSCC rising rapidly.2
Patient Demographics and Clinical Characteristics
It is interesting that HPV-positivity in the oropharynx patients represent a unique entity, as the HPV-negative OPSCC and all OCSCC patients appear to be similar in demographics. This distinction along with other clinical characteristics of each is summarized below ( Table 1).
Table 1 . Common Demographics and Clinical Characteristics of OCSCC and OPSCC
Diagnosis
The initial workup of these patients involves a physical exam, visualizing the primary tumor by fiberoptic endoscopy in the outpatient clinic, and sampling the primary tumor with a tissue biopsy or neck mass with fine needle aspiration to confirm the disease. Currently, testing for HPV status is routine for oropharyngeal lesions, immunostaining for p16 protein (surrogate marker) being the most popular method. Moreover, when encountering neck masses proven to be squamous cell carcinoma, p16 testing could be utilized to predict HPV and/or oropharyngeal origin. Following diagnosis, imaging modalities such as MRI, CT, and CT-PET are often utilized to determine the extent of disease, namely, nodal involvement and the presence of distant metastasis.
 
Imaging
Typically, contrasted CT or MRI of the primary lesion and the neck is employed for both OCSCC and OPSCC, with CT-PET reserved for advanced disease. For OPSCC, the authors feel that contrasted CT combined with the CT-PET fusion is a useful and beneficial imaging study that provides information on primary tumor proximity to the lingual neurovascular bundle, the carotid and jugular vascular structures, along with mandible and pterygoid muscles, which aids in accurate staging (Figure 3A). Additionally, contrasted imaging reveals lymph nodes that may be suspicious for harboring metastatic disease even when they are normal by size criteria (Figure 3B). As noted earlier, HPV-positive OPSCC commonly involves the base of tongue (Figure 4A) and advanced nodal disease is more likely present, typically appearing large and cystic (Figure 4B).
Figure 3. Imaging of Advanced OCSCC. A. CT-PET showing uptake of primary gingival SCC involving the mandible (green arrow) with nodal metastasis (yellow arrows) B. Contrast CT showing a lymph node less than 1cm in size (red arrow) with metastatic OCSCC.
Figure 4. Imaging of Advanced OPSCC. A. CT-PET showing uptake of primary base of tongue SCC (green arrow) with nodal metastasis (yellow arrow) B. Contrast CT showing a cystic lymph node (red arrows) with metastatic OPSCC.
Staging
The clinical assessments outlined above then translate to the clinical stage of the cancer. Like most cancers, OCSCC and OPSCC are staged by the TNM (tumor, node, metastasis) staging system, a classification established by the AJCC to categorize cancer patients based on prognostic differences. The resulting alphanumeric code (T 0-4, N 0-3 , M 0-1 ) then corresponds to an overall stage (I to IV).
EMERGING CONCEPTS

Since the implementation of the previous AJCC staging system (7th ed., 2010), treatment standards, patient demographics, and cancer knowledge have evolved. A number of these findings relate to improving the accuracy of the staging system, while others shed light on future strategies to undertake the HPV-positive OPSCC epidemic. Changes in staging have resulted from studies revealing prognostic indicators that impact treatment, locoregional control, and survival.

Oral Cavity Cancer
Findings related to OCSCC vary,8-12 though notably, the depth of invasion (DOI) of the primary tumor was found to be an independent prognostic measure for both nodal metastasis and survival in OCSCC.13-15 The DOI is measured histologically by utilizing the basement membrane of normal adjacent tissue as reference. Incorporating the DOI by increments of 5mms helps to categorize patients by survival more effectively compared to the 7th ed. staging system.13,14
Oropharyngeal Cancer
Evidence supporting changes related to OPSCCs has been far more drastic. The stark contrasts in clinical disease behaviors and prognoses between HPV-positive and HPV-negative OPSCCs have caused the 7th ed. staging to prove ineffective. This is based on the account of the increase in HPV-positive disease, which tends to have smaller primary tumors and more advanced nodal involvements.16 Due to these clinical characteristics, HPV-positive patients are frequently given the diagnosis of advanced stage OPSCC, though outcomes are much more favorable compared to their HPV-negative counterpart.17,18 Evidence now reveals that previous classifications of nodal disease as well as local invasiveness in HPV-positive OPSCC must be reconsolidated to more accurately reflect prognostic differences between disease stages.18 These observations, in addition to numerous others, have led to the proposition for a separate staging system for HPV-related OPSCCs.17-24

Extranodal Extension
The presence of extranodal extension (ENE) is defined as the extension of malignancy through the capsule of an affected lymph node. Depending on its severity, it could be recognized clinically, radiographically, or histologically. It's known to be a poor prognostic marker indicating an increased likelihood of regional recurrence and distant metastasis, and as a result, propositions for its addition to the staging system have been made.25,26 Interestingly, ENE is not as predictive of a negative outcome in HPV-positive OPSCC as it is in HPV-negative OPSCC and other HNSCC sites.27

HPV Vaccination
High-risk HPV serotypes (16 and 18) are well known for causing cancers at various sites, namely the cervix, resulting in the development of a number of effective adolescent-administered vaccines. The question as to whether they translate, if at all, to the prevention of HPV-associated OPSCC is logical, but would be substantially difficult to study. However, there are implications of their benefit, and therefore, adolescents of both genders are recommended vaccination.28

At the same time, other novel vaccines with the potential to prevent and even treat HPV-positive HNC are in the works. Many of these approaches are in their infancy and manipulate HPV's E6 and E7 proteins, the core of the virus' tumorigenic virulence.29,30 Injections containing genetically modified HPV-positive cancer cells and E6 and E7-fused proteins are some future developments that may hold promise.31-34
THE NEW STAGING SYSTEM (8th ed.) 
A rigorous review of the accumulating data has resulted in the 8th iteration of the AJCC staging system (2017), major modifications for which are outlined below (Table 2)35. It is also imperative to note the separate clinical and pathological TNM stage grouping systems unique to HPV-positive OPSCC. In brief, clinical Stage I category is expanded to include T0-T2 with cN0-N1 disease, while T3 or cN2 disease would upstage to clinical Stage II, and T4 or cN3 disease would upstage to clinical Stage III. Similarly, T0-T2 with pN0-N1 disease is considered pathological Stage I, however, pathological Stage II is rearranged to include T3-T4 with pN0-N1 and T0-T2 with pN2 conditions, and pathological Stage III is limited to T3-T4 with pN2 disease. Of note, clinical and pathological Stage IV disease is only determined by the presence of distant metastasis (M1) and pathological N3 no longer exists.35 
Table 2. Summary comparing 7th and 8th ed. AJCC staging of OCSCC and OPSCC 34
DOI - depth of invasion, LN - lymph node, ENE(+) - extranodal extension present, ENE(-) extranodal extension absent, ipsi - ipsilateral, bi - bilateral, ctr - contralateral  
CHANGES IN MANAGEMENT

Current therapies for OCSCC and OPSCC include isolated or various combinations of surgery, radiation therapy, chemotherapy, and immunotherapy. The management has historically been stage-dependent, with therapies increasing in intensity with higher stage. In general, all OCSCCs are treated with surgery unless metastatic, unresectable, or there are contraindications to surgery. However, OPSCC can be treated with surgery (transoral robotic surgery) or radiation therapy alone for early stage (I or II) while combined therapy using surgery plus radiation therapy or chemoradiation is the standard for advanced stage (III or IV). 36,37 However, recent evidence suggests the need to individually tailor treatment practices as overtreatment has been a topic of concern, particularly for early-stage OCSCCs and OPSCCs. 18,38 Consequently, prospective studies are currently underway to minimize morbidities and de-intensifying treatment in patients undergoing aggressive multimodal regimens. 23
SUMMARY

OCSCC and OPSCC are clinically and pathologically distinct diseases. While the overall decrease in incidence of all HNCs is favorable, the rise in HPV-positive OPSCCs has become an important issue in the diagnosis, prevention, and treatment of these cancers. This evolving landscape in the modern era has culminated in the release of the 8th ed. of the AJCC staging system, which incorporates critical parameters to improve prognostic categorization. Highlights include the incorporation of depth of invasion in oral tongue cancers, separation of OPSCC staging by HPV status, and inclusion of extranodal extension in nodal staging. By more accurately reflecting the differences in patient prognoses, cancer management is sure to adapt with time. Furthermore, translational research is showing potential in the realm of HPV prevention, diagnostics, and unique therapeutics, adding to the collective efforts to tackle this epidemic.
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Terry A, Day, M.D.

Wendy and Keith Wellin Endowed Chair in Head & Neck Surgery
Professor and Director,
Division of Head & Neck Oncology
M.D.: University of Oklahoma College of Medicine
Residency: Louisiana State University Medical Center
Fellowship: University of California, Davis, for Head & Neck Oncologic Surgery
   University of Bern in Switzerland for Craniomaxillofacial Surgery 
Special Interests: Head & Neck tumor surgery, microvascular reconstructive surgery, skull base surgery
Email: dayt@musc.edu
E-Update Articles 
Look for these articles in upcoming issues 

December:
Status of Sustained Release Dexamethasone in Treating Meniere's Disease

January:
Caustic Ingestion in Children

February:
Facial Plastic & Reconstructive Surgery

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