Staging of Human Papilloma Virus (HPV) related cancers of the Oropharynx

Abstract

For the past two decades an increasing number of oropharyngeal cancers have been found to be associated with the human papilloma virus (HPV). These tumors are a biologically distinct entity with better prognosis and excellent response to therapy. Therefore, a separate staging system has been introduced for HPV-related oropharyngeal tumors in the latest edition of the American Joint Committee on Cancer (AJCC 8^th Ed).

Introduction:

To accurately stage cancer is of extreme importance in order to select the best treatment options for each individual patient, assess prognosis and compare outcomes data across institutions, geographic regions and treatment modalities. Since the discovery that a subset of oropharyngeal cancers is related to the human papilloma virus (HPV), the knowledge about this unique entity has grown exponentially,[1]-[3] and the incidence is continually increasing worldwide.[4]-[7] In addition, due to the observation of a biologically distinct and favorable natural history and excellent response to therapy for HPV-related cancers, a separate staging system has been introduced for these tumors in the latest edition of the American Joint Committee on Cancer (AJCC 8^th Ed).[8], [9]

Rationale for a specific HPV-related oropharynx cancer staging system:

There are multiple facts that led to the development of a separate staging system for HPV-positive tumors. First, they have a different biological behavior, with excellent response to therapy, and generally better oncological outcomes when compared to HPV-negative tumors.[10]-[14] Second, they differ epidemiologically, being associated with sexual behaviors and having a higher percentage of younger patients and a lower percentage of patients with history of tobacco use.[15], [16]

The T classification for the primary tumors remains the same as that used for the HPV-negative tumors. However, there are changes in the N classification, since the implications of nodal involvement, one of the strongest prognostic factors in HPV-negative head and neck cancer, are not the same. For HPV-positive tumors, nodal involvement is not as detrimental.[17] Moreover, the number of metastatic lymph nodes is the most important predictor of outcomes, surpassing the influence of lymph node size, laterality and extranodal extension (ENE).[18]-[21]

Supporting data:

Multiple studies have shown the differences in prognosis based on HPV status in oropharyngeal tumors, which later on led to the need for developing a separate staging system for HPV-positive oropharyngeal tumors. This change in the latest AJCC staging system was mainly supported by the study published by the International Collaboration for Oropharyngeal Cancer Network for Staging (ICON-S) group, which is comprised of five North American and two European centers, and by data from the Washington University School of Medicine.[20], [22], [23]

Methods to stage a patient as HPV-positive:

For staging purposes, an oropharyngeal tumor is considered HPV-positive based on p16 overexpression in immunohistochemistry (IHC), which acts as a surrogate marker.[24], [25] The AJCC selected this method due to its wide availability around the world and lower cost. Alternatively, HPV in situ hybridization (ISH) can be used, which is a more specific test, but is expensive and may not be available in some parts of the world. If neither p16 IHC or HPV ISH are available for an oropharyngeal cancer, the patient should be staged following the p16-negative oropharyngeal staging system.[9]

The pattern to consider p16 positivity by IHC is a strong diffuse expression (described as +2/+3 intensity and ≥ 70-75% distribution). Nuclear staining needs to be present, which can be accompanied or not by cytoplasmic staining.[9]

The standard of care nowadays is to test all oropharyngeal cancers for p16 to adequately classify patients into HPV-positive vs HPV-negative tumors given the fact that the implications on management are different.

Changes in the T classification:

The main T categories have not changed, being the same as oropharyngeal tumors staged by the AJCC previous edition (7^th Ed),[26] regardless of HPV status, and also being the same for both clinical and pathological classifications. The only difference is that HPV-related tumors will not include an “in situ” category (Tis) and that T4b will no longer exist.[9]

Changes in the N classification:

In terms of nodal disease, for HPV-positive tumors, there is a different classification for clinical and pathological staging. In all other mucosal squamous cell carcinomas of the upper aerodigestive tract, and not related to HPV, ENE is considered a strong prognostic factor, which upstages the N stage. However, the role of ENE has been shown to be less important in HPV-related tumors, and therefore it is not considered when assigning N stage to these tumors.[19]-[21]

For the clinical classification, laterality and size of the lymph nodes are taken into account. Besides NX and N0, there are still the main 3 categories for those patients with positive lymph nodes (N1, N2 and N3), however, subclassification of N2 into N2 a, b and c is removed. For patients with lymph nodes smaller than 6 cm, if they are all ipsilateral they are categorized as N1, and contralateral or bilateral positive lymph nodes are staged as N2, regardless of number of positive nodes. The N3 category is reserved for any metastatic node larger than 6cm, regardless of the number of positive nodes or laterality.[9]

On the other hand, for the pathological N staging, only number of positive lymph nodes are considered. Obviously, pathological staging is possible only in patients who are treated surgically. Besides pNX and pN0, only 2 categories are considered for patients with positive lymph nodes. If there are 4 or less metastatic lymph nodes it would be classified as pN1, and if there are more than 4 metastatic lymph nodes as pN2. No pN3 category is used in HPV-positive tumors. The rationale for the latter category to disappear is that in the data used to support the new staging, N3 tumors had equivalent outcomes to N1 tumors in the cohort treated surgically. This change was only applicable to the pathological staging since the favorable outcomes of N3 disease were not seen in the clinical dataset.[9]

It is important to highlight that these tumors are more likely associated with cystic lymph nodes. Therefore, we need to carefully assess these patients with a computerized tomography (CT) or the CT component of a positron emission tomography (PET)/CT, since sometimes the fluorodeoxyglucose (FDG) uptake of these nodes is decreased or even absent in cystic lymph nodes. This feature can also sometimes cause confusion in the diagnosis, being wrongly categorized as branchial cleft cysts.[27]

Cervical metastasis of unknown primary:

Another addition in the new 8^th edition of the AJCC staging system, is that cervical metastases of unknown primary located in levels II/III should be tested for p16 IHC, and if they show positivity and the histology is consistent with features of HPV-positive tumors, such as basaloid features, they should be considered an HPV-related tumor and therefore be classified according to the oropharynx HPV-positive staging system. Although in this case, it is also recommended to test for HPV and Epstein-Barr virus-encoded small RNAS (EBER) using ISH to further confirm that the tumor is HPV-related and not of Epstein-Barr virus origin. The latter would suggest a primary tumor of the nasopharynx and staging according to this site should be used.[9]

Changes in the AJCC prognostic stage groups:

In terms of the clinical stage groups, now, for HPV-positive oropharyngeal carcinomas, stage I encompasses all T0, T1 or T2 that are N0 or N1, and stage II is reserved for those T0, T1 or T2 that are N2 or T3 that are N0, N1 or N2. Stage III is reserved for N3 tumors, regardless of T classification, and T4 regardless of N classification. And finally, Stage IV is assigned to patients with distant metastasis (M1).[9]

For pathological stage, stage I is the same as the clinical stage. Stage II includes patients with T0, T1 or T2 that are N2 and those with T3 or T4 and N0 or N1. Stage III encompasses patients with T3 or T4 and N2, and again, stage IV is reserved for those with M1 disease.[9]

Performance of the AJCC 8^th Edition staging system for HPV-positive tumors:

After the publication of the AJCC 8^th Edition, multiple studies have validated the better performance of this staging system when compared with previous editions where HPV-positive tumors were grouped with all pharyngeal cancers.[28]-[33] These studies have given robustness to this change, which has been widely accepted in the head and neck oncology field.

Goals for future staging editions:

We have significantly improved the staging of HPV-related tumors by creating a separate classification. However, more refinements can be done to more accurately predict outcomes in this group of patients. We envision incorporating into the staging system additional prognostic factors to have a more comprehensive view of each specific patient, considering not only tumor but also host characteristics, and developing personalized predictive nomograms for each patient.

Conclusions:

A specific staging system for HPV-positive oropharyngeal tumors has been introduced in the latest AJCC staging system (AJCC 8^th Ed). This addition has been shown to significantly improve how these patients are stratified into staging groups, with a better prediction of their oncological outcomes.

Although we have already done a huge step forward in the assessment and risk stratification of HPV-positive tumors, we still have room for improvement. Future editions of the staging system will try to incorporate even more changes to offer the best care for oropharyngeal cancer patients and provide more accurate individual predictive tools.

Data availability statement:

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.

Synopsis:

A separate staging system has been introduced for human papilloma virus (HPV)-related oropharyngeal tumors in the latest edition of the American Joint Committee on Cancer (AJCC 8^th Ed). In this article we summarize the rationale behind this addition and the changes that have been incorporated.