TNM Staging of Oropharyngeal Cancer – Updates in AJCC 8th Edition

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
Tis Removed Carcinoma institu
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(+)

Composite/Overall staging

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
T Staging N0 N1 N2a,b,c N3a,b
T1 I III IVa IVb
T2 II III IVa IVb
T3 III III IVa IVb
T4a IVa IVa IVa IVb
T4b IVb IVb IVb IVb
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
T Stages cN0 pN0 cN1 pN1 cN2 pN2 cN3
T0 NA NA I I II II III
T1 I I I I II II III
T2 I I I I II II III
T3 II II II II II III III
T4 III II III II III III III
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.

References

  1. 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.
  2. 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.
  3. 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.

Meet the author

Dr Sanu P Moideen is an Indian-born oto-rhino-laryngologist (ENT) based in Cochin, Kerala, India. He is currently working as Post-Doctoral Fellow in Head and Neck Oncology at Regional Cancer Center, Trivandrum, Kerala.

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