The recently released 8th edition of the American Joint Committee on Cancer (AJCC) Staging Manual, Head and Neck Section, introduces significant modifications from the prior 7th edition.
In the head and neck domain, the most significant update creates a separate staging algorithm for high-risk human papillomavirus (HPV)-associated cancer of the oropharynx, distinguishing it from oropharyngeal cancer (OPC) with other causes.
This article describes several of the most significant modifications in the staging of oropharyngeal cancer, and the rationale for the revisions, to alert the reader to the evolution of the field.
Why separation to HPV positive and negative groups?
When analyzing the data on oropharyngeal cancers, it was found that 60-80% of oropharyngeal cancer cases are HPV positive. These studies have shown a significant difference in the clinical spectrum between HPV +ve and HPV -ve oropharyngeal cancers. Some of these characteristics are tabulated below.
|HPV Positive||HPV Negative|
|Age group||Younger, healthy patients – median age 57 years||Median age 61 years|
|Tobacco exposure||Little or no tobacco exposure||Most with a history of tobacco exposure|
|Clinical presentation||Small primary, large nodal disease||Large primary, small or large nodal disease|
|T stage at presentation||64% at early T stages||44% at early T stages|
|N stage at presentation||69% as advanced neck disease||51% as advanced neck disease|
|Prognosis||Excellent||Poor compared with HPV positive|
|Chance of 2nd primary||Less||More|
From the table, it’s clear that HPV positive oropharyngeal cancers are associated with a good prognosis and less chance of recurrence. This was the whole rationale behind creating a separate staging algorithm for high-risk human papillomavirus-associated oropharyngeal cancer.
p16 is a surrogate molecular marker for detecting HPV infection. Based on the expression of p16, oropharyngeal cancers are divided into p16 positive(HPV positive) and p16 negative (HPV negative).
Changes in T Staging
In TNM staging of cancer, T describes the size of the original (primary) tumor and whether it has invaded nearby tissue.
The following are changes made in T classifications of oropharyngeal cancers.
For a p16 negative OPC
- T0 in AJCC 7 was removed. This is because, in a p16 negative cancer, if no primary lesion can be identified, then the lymph node may have emanated from any mucosal site. So there is no rationale to support retaining the T0 designation outside of the virally associated cancers of the oropharynx.
For a p16 positive cancer
- Carcinoma in situ (Tis) stage of AJCC 7 removed due to the absence of a distinct basement membrane in the epithelium of Waldeyer’s ring and also due to the indolent nature of p16 + oropharyngeal cancer.
- T4a / T4b distinction eliminated as prognostically there is no difference – means survival curves of T4a and T4b are indistinguishable.
|Primary tumor (T)||p16 positive||p16 negative|
|Tx||Removed||Primary tumor cannot be assessed|
|T0||No primary identified||Removed|
|T1||Tumor 2 cm or smaller in greatest dimension|
|T2||Tumor larger than 2 cm but not larger than 4 cm in greatest dimension|
|T3||Tumor larger than 4 cm in greatest dimension or extension to the lingual surface of epiglottis|
|T4||Moderately advanced local disease. Tumor invades the larynx, extrinsic muscle of tongue, medial pterygoid, hard palate, or mandible or beyond||T4a||Tumor invades the larynx, extrinsic muscle of tongue, medial pterygoid, hard palate, or mandible or beyond.*|
|T4b||Removed||Very advanced local disease.
Tumor invades lateral pterygoid muscle, pterygoid plates, lateral nasopharynx, or skull base or encases carotid artery.
Changes in N staging
Nodal stages are divided into clinical nodal (cN) staging and pathological (pN) nodal staging.
- Clinical nodal staging is established after clinical examination and basic investigations like imaging, needle aspiration, etc. It is based on the laterality and size of nodes.
- Pathological nodal (pN) staging is established after the pathological evaluation of the surgically dissected specimen. It is based on the number of lymph nodes identified in the surgical specimen and ENE status of nodes.
cN classification for p16 negative tumors.
With the exception of the inclusion of extranodal extension, cN classification for p16 negative tumors remains unchanged.
N3 nodes are now divided into N3a and N3b.
- Any metastatic lymph node more than 6cm in dimension, but no ENE is staged as N3a.
- Any lymph node with ENE, irrespective of its size or laterality is considered as N3b with poor prognosis.
cN classification for p16 positive cancer
“Multiple lymph nodes do not change the good prognosis of HPV related oropharyngeal cancer compared with a single node.”
N staging for p positive cancers is now simplified. The number of metastatic lymph nodes is no longer significant in HPV positive cases. Instead, the size and laterality only matter in clinical staging.
- Ipsilateral lymph nodes < 6 cm in size, regardless of number, had a similar impact on survival and are staged as N1.
- Bilateral or contralateral lymph nodes (< 6 cm, regardless of number) has a worse outcome than N1. Therefore, contralateral or bilateral lymph nodes are classified as N2.
- Any lymph node with a size of more than 6 cm has the worst survival. These are grouped as N3.
- There is no N3a or N3b in p16 positive cancers. ENE is not considered as a prognostic factor in these cases.
|Clinical N (cN)||p16 positive||p16 negative|
|NX||Regional lymph nodes cannot be assessed|
|N0||No regional lymph node metastasis|
|N1||One or more ipsilateral lymph nodes, none larger than 6 cm||Metastasis in a single ipsilateral lymph node, 3 cm or smaller in greatest dimension and ENE(–)|
|N2||Contralateral or bilateral lymph nodes, none larger than 6 cm||N2a||Metastasis in a single ipsilateral node larger than 3 cm but not larger than 6 cm in greatest dimension and ENE(–); or|
|N2b||Metastases in multiple ipsilateral lymph nodes, none larger than 6 cm in greatest dimension and ENE(–); or|
|N2c||In bilateral or contralateral lymph nodes, none larger than 6 cm in greatest dimension and ENE(–)|
|N3||Lymph node(s) larger than 6 cm||N3a||Metastasis in a lymph node larger than 6 cm in greatest dimension and ENE(–); or|
|N3b||Metastasis in any node(s) and clinically overt ENE(+)|
pN staging for p16 negative cancer
As said above, p staging obviously applicable only to patients who undergo surgery. But the role of surgery in oropharyngeal cancers is limited.
pN staging for p16 positive cancer
- Though the size and laterality of lymph nodes have no prognostic implication in clinical N staging, it has got an impact on survival when coming to pN staging. This has resulted in the introduction of 2 separate composite staging systems, one for cTNM and one for pTNM – read below.
- The number of pathologically positive lymph nodes yielded survival differences, the cutoff was at 4.
- ENE is not considered in p staging for HPV positive OPC.
|Pathological N (pN)||p16 positive||p16 negative|
|Nx||Regional lymph nodes cannot be assessed|
|pN0||No regional lymph node metastasis|
|pN1||Metastasis in 4 or fewer lymph nodes||Metastasis in a single ipsilateral lymph node, 3 cm or smaller in greatest dimension and ENE(–)|
|pN2||Metastasis in more than 4 lymph nodes||pN2a||Metastasis in single ipsilateral or contralateral node 3 cm or smaller in greatest dimension and ENE(+) or|
|a single ipsilateral node larger than 3 cm but not larger than 6 cm in greatest dimension and ENE(-)|
|pN2b||Metastasis in multiple ipsilateral nodes, none larger than 6 cm in greatest dimension and ENE (-)|
|pN2c||Metastasis in bilateral or contralateral lymph nodes, none larger than 6 cm in greatest dimension and ENE(-)|
|pN3a||Metastasis in a lymph node larger than 6 cm in greatest dimension and ENE(-)|
|pN3b||Metastasis in a single ipsilateral node larger than 3 cm in greatest dimension and ENE(+);or|
|multiple ipsilateral, contralateral or bilateral nodes,any with ENE(+)|
For p16 negative cancers
- Overall staging remains unchanged for p16 negative. As ENE is now N3b, a higher proportion of oropharyngeal cancer patients are in stage IVb group.
|Anatomic Stage and Prognostic Groups for Clinical and Pathologic TNM Grouping of Non-Human Papillomavirus-Associated (p16-Negative) Oropharyngeal Cancer, 8th Edition Staging Manual|
|Any M1 is stage IVC.|
For p16 positive cases
Drastic changes are there for p16 positive oropharyngeal cancer.
- As mentioned above in the N staging system, 2 different composite staging systems are introduced for HPV positive OPC, which is tabulated below.
- Stage III is now reserved for bulky tumors (T3/T4) and multiple nodes (5+)
- Stage IV reserved only for M1 disease, a group known to have much poorer survival.
|Anatomic Stage and Prognostic Groups for Clinical and Pathologic TNM Grouping of Human Papillomavirus-Associated (p16-Positive) Oropharyngeal Cancer, 8th Edition Staging Manual|
|Any M1 is stage IV|
Based on the new classification system, most previous stage IVA oropharyngeal cancers are now staged I or II with a good prognosis. For example, a patient that presents with a 2 centimeter, p16+ tonsil cancer and 2 positive lymph nodes in the same side neck (T2N2b) is stage IV in the 7th Edition Staging Manual but will become a stage I in the 8th Edition.
The new staging will give a much more accurate and reasonable prediction of survival for newly diagnosed patients.
- Lydiatt WM, Patel SG, O’Sullivan B, Brandwein MS, Ridge JA, Migliacci JC, Loomis AM, Shah JP. Head and neck cancers—major changes in the American Joint Committee on cancer eighth edition cancer staging manual. CA: a cancer journal for clinicians. 2017 Mar;67(2):122-37.
- Wittekindt C, Gültekin E, Weissenborn SJ, Dienes HP, Pfister HJ, Klussmann JP. Expression of p16 protein is associated with human papillomavirus status in tonsillar carcinomas and has implications on survival. InCurrent Research in Head and Neck Cancer 2005 (Vol. 62, pp. 72-80). Karger Publishers.
- Stephen JK, Divine G, Chen KM, Chitale D, Havard S, Worsham MJ. Significance of p16 in site-specific HPV positive and HPV negative head and neck squamous cell carcinoma. Cancer and clinical oncology. 2013;2(1):51.