HEAD & NECK CME

ABBREVIATION KEY
7th Edition ⫽ American Joint
Committee on Cancer 7th Edition
Cancer Staging Manual
8th Edition ⫽ American Joint
Committee on Cancer 8th Edition
Cancer Staging Manual
AJCC ⫽ American Joint Committee
Overcoming “Stage” Fright: American on Cancer
cENE ⫽ clinically overt extranodal
Joint Committee on Cancer 8th extension
EBV ⫽ Epstein-Barr virus
EBV⫹ ⫽ tests positive for EBV
Edition Pharyngeal Cancer Update EBV⫺ ⫽ tests negative for EBV
ENE ⫽ extranodal extension
J.M. Yetto, A. Germana, M.P. Bauer, J.R. Foley, P.A. Moullet, and M.R. Cathey ENE(⫹) ⫽ positive for ENE
ENE(⫺) ⫽ negative for ENE
HPC ⫽ hypopharyngeal cancer
HPV ⫽ human papillomavirus
NPC ⫽ nasopharyngeal carcinoma
OPC ⫽ oropharyngeal squamous cell
CME Credit cancer
The American Society of Neuroradiology (ASNR) is accredited by the Accreditation Council for Continuing Medical Education p16⫺ ⫽ p16 underexpression or no
(ACCME) to provide continuing medical education for physicians. The ASNR designates this enduring material for a maximum of 1 AMA
expression
PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity. To
obtain Self-Assessment CME (SA-CME) credit for this activity, an online quiz must be successfully completed and submitted. ASNR p16⫹ ⫽ p16 overexpression
members may access this quiz at no charge by logging on to eCME at http://members.asnr.org. Nonmembers may pay a small fee to pENE ⫽ pathologically proven
access the quiz and obtain credit via https://members.asnr.org/webcast/content/course_list.asp?srcNeurographics. Activity Release extranodal extension
Date: April 2019. Activity Termination Date: April 2022. rENE ⫽ radiologically overt
extranodal extension
TNM ⫽ tumor, node, metastasis

ABSTRACT
Significant changes to the staging system for pharyngeal cancers are contained within the Received August 31, 2018; accepted
February 4, 2019.
recently implemented American Joint Committee on Cancer 8th Edition Cancer Staging
From the Department of Radiology
Manual and reflect current prognoses and treatment options. This article reviews changes (J.M.Y., M.P.B., J.R.F., P.A.M., M.R.C.),
particularly relevant to radiologists and highlights the critical role that radiologists play in Naval Medical Center San Diego, San
Diego, California, and Department of
the diagnosis and staging of head and neck cancer. By using multimodality case examples, Radiology (A.G.), Naval Medical Center
nasopharyngeal, oropharyngeal, and hypopharyngeal carcinomas are emphasized as well Camp Lejeune, Camp Lejeune, North
Carolina.
as the newly described entity of radiologically overt extranodal extension.
Previously presented at the 56th
Learning Objectives: 1) Compare the American Joint Committee on Cancer 7th Edition descrip- American Society of Neuroradiology
Annual Meeting in June 2–7, 2018,
tion of T4 disease versus the 8th edition description of T2 disease for nasopharyngeal carci- Vancouver, BC, Canada.
noma, 2) explain the relationship between the Epstein-Barr virus and nasopharyngeal carci- The views expressed in this article
noma as well as the human papillomavirus and p16⫹ oropharyngeal cancer, and 3) describe the are those of the authors and do not
necessarily reflect the official policy
impact of extranodal extension on clinical staging for cervical nodal metastasis in the setting of or position of the Department of
an unknown primary tumor, as well as for p16⫺ oropharyngeal and hypopharyngeal cancers. the Navy, Department of Defense,
or the United States government.
The authors are military service
members. This work was prepared
INTRODUCTION information that affects prognosis be- as part of official duties. Title 17
Cancer staging refers to the process of de- comes evident. Historically, the AJCC U.S.C. 105 provides that “copyright
protection under this title is not
scribing the extent of cancer at a certain TNM staging system has been revised ev- available for any work of the
time point, and it is used to predict patient ery 5 to 7 years; however, because the sci- United States Government.”
prognosis and define treatment.1 The tu- ence of cancer staging is increasingly evolv- Please address correspondence to
Joseph M. Yetto, MD, Department
mor, node, and metastasis (TNM) staging ing, the AJCC expects more frequent of Radiology, Naval Medical Center
system was developed as a collaborative revisions in the future.1 San Diego, 34800 Bob Wilson
Drive, San Diego, CA 92134;
effort between the American Joint Com- The AJCC TNM staging system is bro- e-mail: jmyettojr@gmail.com.
mittee on Cancer (AJCC) and the Union ken up into several classifications based on http://dx.doi.org/10.3174/ng.1800046
for International Cancer Control; it is con- certain time points in a patient’s care con- Disclosures
sidered the most clinically useful staging tinuum. Specifically, there are 5 major Based on information received
from the authors, Neurographics
system.1 The AJCC TNM staging system is TNM staging classification schemes: clini- has determined that there are no
periodically updated and revised as new cal, pathological, posttherapy, recur- Financial Disclosures or Conflicts of
Interest to report.
clinical, pathological, biological, and other rence, and autopsy.1 Although radiology is

96 兩 Neurographics 2019 March/April;9(2):96 –110; www.neurographics.org

Table 1A: Summary of 8th edition unknown primary clinical staging classification changes

Definition of regional lymph node (N)
Definition of regional lymph node (N)
ENE in HPV-unrelated cancers
Classification of ENE
Occult primary tumor
Note:—Adapted from Ref 6.
ENE ⫽ extranodal extension.
ENE(⫹) ⫽ positive for ENE.
ENE(⫺) ⫽ negative for ENE.
Separate N staging approaches have been described for HPV-related and HPV-unrelated cancers
ENE is introduced as a descriptor in all HPV-unrelated cancers
Only clinically and rENE should be used for clinically staging the N category.
Clinically overt ENE is classified as cENE and is considered ENE(⫹) for the clinically staged N category
Staging of the patient who presents with EBV-unrelated and HPV-unrelated cervical nodal metastasis
is now included in this chapter

Table 1B: New 8th edition TNM clinical staging system for the unknown Table 1C: New 8th edition unknown primary prognostic stage groups
primary Stage
Category *NEW* 8th Edition Unknown Primary
M0
T Primary tumor
T0, N1 III
T0 No primary tumor identified with EBV⫺ and p16⫺ T0, N2 IVA
cervical nodal metastasis
T0, N3 IVB
N Regional lymph nodes
M1
NX Regional lymph nodes cannot be assessed
T0, any N IVC
N0 No regional lymph node metastasis
Note:—Adapted from Ref 6.
N1 Metastasis in a single ipsilateral lymph node, no ⬎ 3 cm M0 ⫽ no distant metastasis.
in greatest dimension and ENE(ⴚ) M1 ⫽ distant metastasis.

N2a Metastasis in a single ipsilateral lymph node ⬎ 3 cm but

not ⬎ 6 cm in greatest dimension and ENE(ⴚ)
N2b Metastases in multiple ipsilateral nodes, none ⬎ 6 cm in
greatest dimension and ENE(ⴚ)
N2c Metastases in bilateral or contralateral nodes, none ⬎ 6
cm in greatest dimension and ENE(ⴚ)
N3a Metastasis in a lymph node ⬎ 6 cm in greatest
dimension and ENE(ⴚ)
N3b ENE(ⴙ)
Note:—Adapted from Ref 6.
ENE ⫽ extranodal extension.
ENE(⫹) ⫽ positive for ENE.
ENE(⫺) ⫽ negative for ENE.
EBV ⫽ Epstein-Barr virus.
EBV⫹ ⫽ tests positive for EBV.
EBV⫺ ⫽ tests negative for EBV.
useful for all TNM staging classifications, this review article
focused on the clinical stage classification. Clinical stage
classification is based on the patient’s presentation, physi-
cal examination, and medical history. Although not re-
quired, when imaging is performed, it is included in clinical
staging. Similarly, although not required, when regional
lymph node sampling is performed, the results may be in-
cluded in the clinical stage classification.
The TNM staging system is primarily based on the an-
atomic extent of cancer supplemented by nonanatomic fac-
tors for certain cancers, such as an association with Epstein-
Barr virus (EBV) or human papillomavirus (HPV).1 The T is
defined by the size and/or contiguous extension of the pri-
mary tumor, and the role of the size component is specifi-
cally defined for each cancer site. N is defined by the absence
or presence of regional lymph nodes that contain neoplastic
elements. Other features pertinent to category N include the
number of regional lymph nodes involved, the maximum
size of nodal metastasis, and the presence or absence of
extranodal extension (ENE). Apart from ENE, which is
discussed below in the Lymph Node and ENE section, these
are defined for each cancer site. M is defined as the absence
or presence of neoplastic elements beyond the local tumor
bed or expected regional lymph nodes.
On January 1, 2018, the AJCC 8th Edition Cancer Stag-
ing Manual (8th Edition) took effect and introduced several
significant changes and additions to the staging of head and
neck cancers.1-3 Broadly, with regard to staging head and
neck cancers of the pharynx, the pharynx is now divided
into 3 distinct chapters: Nasopharynx, HPV-mediated
(p16⫹) Oropharyngeal Cancer, and Oropharynx (p16⫺)
and Hypopharynx.1 The change is based on the interplay
between anatomy, disease epidemiology, and biology.2-4
Accurate staging is a critical element in the treatment for
head and neck cancers. A uniform staging paradigm has
proved to be a key element in understanding and comparing
disease epidemiology as well as the effectiveness of treat-
ments rendered for populations across a variety of institu-
tions.1 For individuals, proper staging directs clinical man-
agement and provides information regarding prognosis,
which allows for personalized treatment plans. As new in-
formation comes to light and our understanding of these
disease processes evolves, staging systems must be reviewed
to ensure the ongoing effectiveness of treatments. Thus,
changes between the AJCC 7th Edition Cancer Staging
Manual (7th Edition) and the 8th Edition reflect this natural
process.1,5 Familiarity with these changes, many of which

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Fig 1. A 33-year-old man presented with a new, palpable neck mass.
High-resolution axial T2 fat saturation image, demonstrating a right-
sided 4.5-cm cystic cervical level IIA lymph node (red arrow). There was
no primary tumor identified within the nasopharynx and oropharynx.
Histopathologic evaluation identified squamous cell carcinoma within
the lymph node.
are quite significant, allows radiologists to continue to play
a critical role in the clinical staging of these diseases.
CERVICAL LYMPH NODES AND UNKNOWN PRIMARY
TUMORS OF THE HEAD AND NECK
In the 7th Edition, the staging of cervical nodal metastasis
with an occult primary tumor was performed by clinicians
who selected what was thought to represent the primary
site. Chapter 6, Cervical Lymph Nodes and Unknown Pri-
mary Tumors of the Head and Neck, is new to the 8th
Edition and is devoted to staging cervical nodal metastasis
with an occult primary tumor, excluding cervical nodal me-
tastasis related to EBV or HPV (Table 1).6 With regard to
head and neck cancer, the single feature that portends the
worst prognosis is the presence of cervical lymph node me-
tastasis, although the degree of impact is relative to the
primary tumor type and the presence of other nonanatomic
factors.6 Also new to the 8th Edition, when the cervical
lymph node metastasis is associated with either EBV or
HPV, then it is staged according the nasopharynx chapter
or HPV-mediated oropharyngeal cancer chapter, respec-
tively.1,7,8 These EBV- and HPV-related cervical nodal me-
tastases respond to treatment differently than other
unknown primary tumor metastasis, which impacts prog-
nosis. That is, viral-mediated cancers respond in the same
manner as their expected occult primary tumor sites. An
unknown primary tumor case that compares the different
clinical staging classification systems and prognostic stage
groups based on EBV and HPV status are featured in Figure
1 and Table 2.
Also new to the 8th Edition is the addition of ENE,
sometimes referred to in the literature as extracapsular
98 兩 Neurographics 2019 March/April;9(2):96 –110; www.neurographics.org
Table 2: Unknown primary tumor 8th edition clinical staging
comparison based on viral status
New 8th Edition
Stage IVA for unknown primary
T0 No primary tumor identified with EBVⴚ AND p16ⴚ
cervical nodal metastasis
N2a Metastasis in a single ipsilateral lymph node ⬎ 3 cm but
not ⬎ 6 cm in greatest dimension and ENE(ⴚ)
M0 No distant metastasis
Stage II for EBV⫹
T0 No primary tumor identified, but EBVⴙ cervical node
involvement
N1 Unilateral metastasis in cervical lymph node, ⱕ6 cm in
greatest dimension, above the supraclavicular fossa
M0 No distant metastasis
Stage I for p16⫹
T0 No primary tumor identified, but p16ⴙ cervical node
involvement
N1 ⱖ 1 ipsilateral lymph nodes, none ⬎ 6 cm
M0 No distant metastasis
Note:—Adapted from Ref 8.
ENE ⫽ extranodal extension.
ENE(⫹) ⫽ positive for ENE.
ENE(⫺) ⫽ negative for ENE.
Staging of the malignancy in Figure 1 may have been challenging without a primary
tumor according to the 7th Edition. In the 8th Edition, this cervical nodal metastasis is
clinically staged according to Chapter 6 unless it is EBV⫹ or p16⫹. According to the
unknown primary chapter, the cancer would be clinical stage IVA. However, if the
cervical node was EBV⫹, then it is presumed to have arisen from the nasopharynx
and would be clinical stage II. This cervical node was actually p16⫹ and, thus, pre-
sumed to have originated from the oropharynx, which corresponds to stage I.
spread, extranodal tumor spread, or extracapsular exten-
sion; to remain consistent with the 8th Edition, this review
article exclusively referred to this entity as ENE.8-12 Given
the importance of lymph node imaging and ENE for all
TNM staging systems, there is a detailed description of both
at the end of this review in the Lymph Node and ENE
section. For now, it is important to know that cervical nodal
metastasis with ENE in an unknown primary tumor (and
unrelated to EBV or HPV) is an extremely poor prognostic
factor that correlates with a nodal category N3b and stage
IVB. In fact, only distant metastasis can worsen the prog-
nostic stage group to stage IVC. Another change in the
unknown primary chapter is that the 8th Edition now in-
cludes different TNM staging classifications for clinical
stage versus pathologic stage.6 This review focused on clin-
ical TNM staging classification and thus the clinical TNM
staging classification versus pathologic stage TNM distin-
guishing features were not discussed in this review.
NASOPHARYNGEAL CARCINOMA
Nasopharyngeal carcinoma (NPC) is unique compared
with other squamous cell cancers of the head and neck
because of its relationship with EBV. NPC is always asso-
ciated with EBV infection in an individual who is geneti-
cally susceptible.13-18 Environmental factors such as alco-
Fig 2. NPC within the left pharyngeal recess. High-resolution axial T2
image demonstrates an NPC (red arrows) expanding the left pharyngeal
recess. The left tensor veli palatini (orange arrow) is anteriorly displaced.
The tumor broadly abuts and indents the left medial pterygoid muscle.

hol and smoking are also known to play a role; these factors
may be amplified in the setting of an EBV infection.13,19-22
There is a bimodal age distribution for NPC, with peaks
in the second and sixth decades of life; however, NPC
most commonly occurs between the ages of 40 and 60
years.8,23-26 NPC is 3 times more common in men than in
women and represents 0.25% of all malignancies in the
United States.8,23-25 NPC is more common in Asia (which
represents 15%–18% of malignancies in southern China)
and Africa, particularly in African children, where NPC
represents 10%–20% of childhood malignancies.23 Al-
though NPC is more common overall in Asia than in Amer-
ica, certain Asian-American subgroups still get NPC at a
higher rate.22,27 For example, the Chinese subgroup dem-
onstrates rates higher than those seen in China and ⬎ 13
times higher than non-Hispanic whites in America.22,27
In addition, there have been studies that identified a ge-
netic predisposition for NPC within Asian subgroups, par-
ticularly in Cantonese and Taiwanese patients.20,22 This
genetic predisposition seems to be related to certain human
leukocyte antigen regions and is believed to alter EBV on-
cogenic properties while increasing individual susceptibility
to environmental carcinogens.20,22 Furthermore, China’s
Guangdong Province has a much higher rate of NPC com-
pared with other Chinese provinces; because the first Chi-
nese immigrants to arrive in America primarily came from
this region, this may account for the increased NPC rates
discussed above.22,28
There are 3 distinct histologic types of NPC recognized
by the World Health Organization.24,25 Keratinizing squa-
mous cell cancer is type 1, which carries the worst prognosis
and is associated with smoking and alcohol.25 Type 1 is
more common in North America, representing 25% of
NPC cases.25 Type 2 is nonkeratinizing squamous cell can-
cer and is the least common in North America and China.25
Type 3 is undifferentiated squamous cell cancer and is the
most common in North America and China, which repre-
sents 63% and 95% of NPC cases, respectively.24,25
Fig 3. NPC perineural tumor spread. A, High-resolution axial and (B)
coronal CT, depicting the foramen ovale (FO) and foramen lacerum (FL),
which are the most common foramina associated with NPC intracranial
extension. The pterygopalatine fossa (PPF) is also highlighted on the
axial CT. C, Coronal contrast-enhanced T1 high-resolution isotropic vol-
ume examination, demonstrating asymmetric widening of the left FO,
with increased enhancement of the left trigeminal nerve mandibular di-
vision (green arrows) due to perineural tumor spread. D, Coronal T1 vol-
ume isotropic turbo spin-echo acquisition postcontrast, demonstrating
an expansile NPC (orange arrows) closely approximating the skull base
with enhancement of the adjacent clivus (yellow arrow), which repre-
sents direct osseous extension of disease.
Fig 4. Pertinent nasopharyngeal anatomy. A and B, Sequential high-res-
olution T2 axial images through the nasopharynx, depicting relevant na-
sopharyngeal anatomy: lateral pterygoid muscle (red arrow), torus
tubarius (white arrow), prevertebral muscle (yellow arrow), tensor veli
palatini (orange arrows), medial pterygoid muscle (pink arrow), pharyn-
geal recess (teal arrow), salpingopalatine fold (blue arrow), and levator
veli palatini (green arrow).
NPC most commonly arises in the fossa of Rosenmüller
(also known as the pharyngeal recess) but may arise any-
where along the lateral pharyngeal wall and frequently in-
volves the torus tubarius (Fig 2).24,25 NPC spreads via direct
extension over mucosal surfaces and through muscles
and/or bone, and readily disseminates via lymphatic drain-
age pathways.24 NPC also has a predilection for perineural
tumor spread; the nerve of the pterygoid canal (Vidian

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Table 3A: Summary of 8th edition NPC clinical staging classification changes

Definition of primary tumor (T)
Definition of primary tumor (T)
Definition of primary tumor (T)
Definition of regional lymph node (N)
Definition of regional lymph node (N)
AJCC prognostic stage groups
AJCC prognostic stage groups
Note:—Adapted from Ref 8.
T0 is added for the EBV⫹ unknown primary with cervical lymph node involvement; the stage group
is defined in the same way as T1 (or TX)
Adjacent muscles involvement (including medial pterygoid, lateral pterygoid, and prevertebral muscles)
is now designated as T2
The previous T4 criteria “masticator space” and “infratemporal fossa” is now replaced by specific
description of soft-tissue involvement to avoid ambiguity
The previous N3b criterion of supraclavicular fossa is now changed to the lower neck (as defined by
nodal extension below the caudal border of the cricoid cartilage)
N3a and N3b are merged into a single N3 category, which is now defined as unilateral or bilateral
metastasis in cervical lymph node(s), ⬎6 cm in greatest dimension, and/or extension below the caudal
border of the cricoid cartilage
The previous substages IVA (T4 N0–2 M0) and IVB (any T N3, M0) are now merged to form IVA
The previous IVC (any T any N M1) is now downstaged to IVB

nerve), a branch of nervus intermedius via the greater su-
perficial petrosal nerve, is the most commonly violated
structure and provides access to both cranial nerves V and
VII.29
Once NPC invades the parapharyngeal space, it may
extend superiorly, inferiorly, or anterolaterally. Superior
extension is the most-frequent route of direct extension and
may result in skull base destruction or spread through the
foramen lacerum or foramen ovale (Fig 3).24 Inferior exten-
sion is usually due to direct submucosal extension and is
often clinically occult. Therefore, radiologists play a partic-
ularly crucial role in defining the extent of submucosal dis-
ease and potential perineural tumor spread, with direct im-
plications on clinical staging and management (Fig 4).
Lateral retropharyngeal lymph nodes are the most com-
mon location for early NPC metastatic disease.24 Although
NPC with ENE does not affect the category N or prognostic
stage group per the TNM staging system, this does consti-
tute locally aggressive disease and warrants discussion in
the radiology report because it may play a role in determin-
ing treatment.30 Furthermore, due to the propensity of NPC
for distant metastasis, the 8th Edition also states, “Meta-
static workup is recommended for patients with node-pos-
itive or locally advanced (T3– 4) disease, those with symp-
toms, signs, and/or biochemical tests suggestive of distant
metastasis.”24,31 Ahmad and Stefani,31 in 1986, published
the incidence of NPC distant metastases based on 256 pa-
tients with NPC, with 63 of them also undergoing autopsy;
they found the overall incidence of distant metastases to be
36%, which went up to 51% on autopsy. When NPC me-
tastasizes distantly, it most commonly involves the lung,
bone, distant lymph nodes, and liver.24,31 Imaging workup
for metastatic disease should include whole-body FDG
PET coupled with CT, contrast-enhanced MR imaging of
the neck, and contrast-enhanced CT of the chest and
abdomen.8
There have been a number of changes to the Nasophar-
ynx chapter that are summarized in Table 3.7,8 Previously,
in the 7th Edition, invasion of the medial and/or lateral
pterygoid muscles and/or prevertebral muscles constituted
a category T4; this is now down-staged to a category T2 in
the 8th Edition. These changes are a direct result of the
AJCC responding to significant controversies identified af-
ter an extensive literature review.8 Specifically, there is
much disagreement in the literature with regard to mastica-
tor space involvement blanketly constituting a category T4,
with a similar controversy surrounding prevertebral muscle
invasion.8,32-34 In 2014, Zhang et al33 analyzed 808 pa-
tients with NPC on MR imaging and concluded that medial
pterygoid invasion should be treated as category T2,
whereas lateral pterygoid invasion may continue to be
treated as a category T4 based on outcomes.
In addition, in 2014, Sze et al34 examined 1104 pa-
tients with nonmetastatic NPC and concluded that NPC
with medial and/or lateral pterygoid invasion alone
should be categorized as T2. These patients had similar
survival rates as patients with category T1 and T2 as well
as significantly better 5-year overall survival compared
with patients with category T3.34 Therefore, what was
previously stage IVA disease at a minimum in the 7th
Edition is now stage II or III disease in the 8th Edition
(Fig 5 and Table 4). There has been the addition of a
category T0 description in the 8th Edition, defined as an
unknown primary tumor in the setting of an EBV⫹ cer-
vical lymph node. This scenario results in clinical staging
according to the NPC chapter vice the unknown primary
chapter, as discussed above.6,8
OROPHARYNGEAL CARCINOMA
Oropharyngeal cancers are one of the most common can-
cers worldwide, with an overall 5-year survival of 50%;
oropharyngeal squamous cell carcinomas (OPC) account
for 90% of oropharyngeal cancers.35-37 Other oropharyn-
geal cancers include minor salivary gland carcinomas, lym-
phomas, and lymphoepitheliomas, which were not dis-
cussed in this review. The OPC incidence is increasing
worldwide due to the dramatic increase in incidence of
HPV, a sexually transmitted infection. HPV-related OPC,

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Table 3B: Comparison between 7th edition and 8th edition TNM clinical staging systems for NPC
Category 7th Edition NPC 8th Edition NPC
T Primary tumor Primary tumor

TX Primary tumor cannot be assessed Primary tumor cannot be assessed

T0 No evidence of primary tumor No primary tumor identified, but EBVⴙ cervical node
involvement
Tis Carcinoma in situ Carcinoma in situ
T1 Tumor confined to the nasopharynx, oropharynx, or nasal fossa Tumor confined to nasopharynx, oropharynx, and/or
nasal cavity without parapharyngeal involvement
T2 Tumor extends to the parapharyngeal space Tumor with extension to parapharyngeal space, and/or
adjacent soft tissue involvement (medial pterygoid,
lateral pterygoid, prevertebral muscles)
T3 Tumor invades bony structures of skull base or paranasal sinuses Tumor with infiltration of bony structures at skull base,
cervical vertebra, and/or paranasal sinuses
T4 Tumor with intracranial extension or involvement of cranial nerves, Tumor with intracranial extension, involvement of
masticator space, orbit, or hypopharynx cranial nerves, hypopharynx, orbit, parotid gland,
and/or extensive soft-tissue infiltration beyond the
lateral surface of the lateral pterygoid muscle
N Regional lymph nodes Regional lymph nodes

NX Regional lymph nodes cannot be assessed Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis No regional lymph node metastasis
N1 Unilateral metastasis in cervical lymph node(s) no ⬎ 6 cm in greatest Unilateral metastasis in cervical lymph node(s) and/or
dimension, above the supraclavicular fossa, and/or unilateral or unilateral or bilateral metastasis in retropharyngeal
bilateral retropharyngeal lymph node(s) no ⬎ 6 cm in greatest lymph node(s), ⱕ6 cm in greatest dimension, above
dimension the caudal border of the cricoid
N2 Bilateral metastasis in cervical lymph node(s) no ⬎ 6 cm in greatest Bilateral metastasis in cervical lymph node(s), ⱕ6 cm in
dimension, above the supraclavicular fossa greatest dimension, above the caudal border of the
cricoid
N3 Metastasis in a lymph node ⬎ 6 cm in greatest dimension or in the Unilateral metastasis in cervical lymph node(s) ⬎ 6 cm
supraclavicular fossa in greatest dimension, and/or extension below the
caudal border of the cricoid
N3a ⬎6 cm in dimension No N3a
N3b Extension to the supraclavicular fossa No N3b
Note:—Adapted from Ref 8.

Table 3C: 8th edition nasopharyngeal carcinoma prognostic stage groups 2 cancer types respond differently to treatment and have a
T0 T1 T2 T3 T4 different prognosis than p16⫹ OPC. These similarities and
differences explain why p16⫺ OPC and HPC are grouped
M0
together, whereas p16⫹ OPC is separated into its own
N0 I II III IVA
chapter in the 8th Edition (Table 5). Both p16⫺ OPC and
N1 II II II III IVA HPC are most commonly associated with smoking and al-
N2 III III III III IVA cohol use.
N3 IVA IVA IVA IVA IVA
There are characteristic imaging and clinical presenta-
tion differences between p16⫹ and p16⫺ OPC.39 The clas-
M1
sic presentation of a p16⫹ OPC is a young adult with a
Any N IVB IVB IVB IVB IVB small exophytic mass that demonstrates well-defined bor-
Note:—Adapted from Ref 8. ders and is associated with large, bulky, and cystic-appear-
M0 ⫽ no distant metastasis.
M1 ⫽ distant metastasis.
ing lymph nodes.40-42 Also, p16⫹ OPC is more likely to
arise from the base of the tongue and has an overall more
also referred to as p16⫹ OPC, has increased in incidence favorable prognosis when compared with p16⫺ OPC.42,43
from 19% in 1987–1990 to 60% in 2005–2006 and is still Results of a number of studies showed that p16⫹ OPC is
on the rise.38 more likely to present at a lower T category and higher N
Traditional OPC, also referred to as p16⫺ OPC, behaves category, and is less likely to have distant metastases com-
similarly to hypopharyngeal cancers (HPC); however, these pared with p16⫺ cancers.40,44-46 However, the typical pre-

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Fig 5. A 55-year-old man with blood in his saliva and a persistent sore throat. A, High-resolution axial CT with contrast, demonstrating an NPC centered
within the right pharyngeal recess (orange arrow) and distorting the right prevertebral muscle (green arrow). B, Small field-of-view axial T1 volume
isotropic turbo spin-echo acquisition (VISTA) postcontrast, demonstrating an enhancing, expansile right-sided NPC (pink arrow), with a tentacle of
tumor (teal arrow) spreading beyond a slip of prevertebral fascia (red arrow). There also is an asymmetric abnormal appearance to the right prever-
tebral muscle (yellow arrow). C, High-resolution axial T2 image, emphasizing the anatomic clinical staging changes between the 7th Edition (left side)
and the 8th Edition (right side). For both sides of this image, the area outlined in green dots represents category T2, whereas the area outlined in pink
dots represents category T4.

Table 4: Comparison of 7th edition versus 8th edition clinical staging
systems for the nasopharyngeal carcinoma that is depicted in Figure 5
7th Edition - Stage IVA for NPC
T4 Tumor with intracranial extension or involvement of cranial
nerves, masticator space, orbit, or hypopharynx
N0 No regional lymph node metastasis
M0 No distant metastasis
8th Edition - Stage II for NPC
T2 Tumor with extension to parapharyngeal space, and/or
adjacent soft tissue involvement (medial pterygoid,
lateral pterygoid, prevertebral muscles)
N0 No regional lymph node metastasis
M0 No distant metastasis
The NPC in Figure 5 would have been stage IVA in the 7th edition but is stage II in the
8th edition.
sentation for p16⫺ OPC is an older adult with a larger mass
that demonstrates ill-defined margins with invasion of ad-
jacent muscles and bone; as might be expected, p16⫺ OPC
carries a worse prognosis overall.41-43
The most common location for OPC is the palatine ton-
sillar region, whether originating within the tonsillar fossa
or the anterior pillar (Fig 6).35,47,48 This location may be
clinically occult, and the tumor often presents as an exophytic
or ulcerative mass. The base of the tongue is another common
primary site, which may also be clinically occult and lead to an
initial presentation at an advanced stage.35,47,48 The posterior
pharyngeal wall is a rare primary site for OPC that presents as
an exophytic mucosal mass, possibly with extension into the
nasopharynx or hypopharynx; it carries the poorest prognosis
with regard to OPC.35
As with NPC, OPC can spread via direct extension over
mucosal surfaces or through muscle and bone, and metas-
tasizes via lymphatic drainage pathways; OPC predomi-
nately drains into the cervical nodal stations II and III as
well as into the medial and lateral retropharyngeal lymph
nodes.9,35 Lymphatic spread is an important prognostic fac-
tor, with 50%–71% of OPC having pathologic lymphade-
nopathy at the time of presentation.9 OPC-related lymph-
adenopathy is most common with the base of the tongue
and tonsillar fossa primary sites (Fig 7 and Table 6).9
P16ⴚ OPC
The classic scenario of p16⫺ OPC is in an older patient with
other comorbidities that potentially limit treatment options
and may worsen an already dismal prognosis.49,50 A p16⫺
OPC is most commonly associated with lifestyle factors,
such as tobacco and alcohol use, with an importance placed
on smoking in pack-years and number of alcohol drinks per
day.51 Overall, the incidence of p16⫺ OPC is declining,
which may reflect the results of antismoking campaigns. At
a molecular level, p16⫺ OPCs more commonly harbor p53
mutations and are more complex tumors, with less response
to all treatment options, including surgery, radiation, che-
motherapy, and targeted agents.2,52 Thus, p16⫺ OPC dem-
onstrates less favorable outcomes due to its overall de-
creased treatment responsiveness compared with p16⫹
OPC.52 There have been a number of changes to the Oro-
pharynx (p16⫺) and Hypopharynx chapter, which are
summarized in Table 5. Again, just as in the unknown pri-
mary tumor chapter, the addition of ENE to the 8th Edition
is reflective of the poor outcomes associated with ENE. A
p16⫺ OPC with ENE represents category N3b, which cor-
responds to a stage IVB. Only distant metastasis can up-
stage ENE to stage IVC.
P16ⴙ OPC
As previously noted, there has been a continued dramatic
increase in the incidence of HPV-mediated cancers of the
tonsil and tongue base.37 The incidence of p16⫹ OPC in-
creased 225% between 1988 and 2004 and, as it continues
to climb, is expected to outnumber the total number of
cases of p16⫹ cervical cancer by 2020.50 HPV is an sexually
transmitted infection with numerous subtypes; HPV 16
and 18 are the most commonly detected high-risk sub-

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Table 5A: Summary of 8th edition p16ⴚ OPC and hypopharyngeal carcinoma clinical staging classification changes

Anatomy–primary site(s) Occult primary tumor: staging of the patient who presents with EBV-unrelated and HPV-unrelated metastatic
cervical lymphadenopathy is not included in this chapter
Definition of primary tumor (T) In hypopharynx, T3 criteria have been changed from “extension to esophagus” to “extension to esophageal
mucosa” T4a criteria now includes invasion of esophageal muscle
Definition of regional lymph node (N) Separate approaches have been described for N categorization for HPV-related and HPV-unrelated cancers
Definition of regional lymph node (N) ENE is introduced as a descriptor in N categorization for all HPV-unrelated cancers
ENE in HPV⫺ unrelated cancers Only clinically and rENE should be used for clinically staging the N category
Classification of ENE Clinically overt ENE is classified as cENE and is considered ENE(⫹) for the clinically staged N category
Note:—Adapted from Ref 7 and 51.
HPV ⫽ human papillomavirus.
HPV⫹ ⫽ cancer caused by HPV.
HPV⫺ ⫽ cancer not caused by HPV.
ENE ⫽ extranodal extension.
ENE(⫹) ⫽ positive for ENE.
ENE(⫺) ⫽ negative for ENE.

types.49,50,53 This disease tends to occur in younger pa-
tients, with fewer comorbidities, and has no known rela-
tionship with alcohol or tobacco use.49,53 Compared with
p16⫺ OPC, individuals with p16⫹ OPC are more likely to
be black men who were never married, although the in-
creasing incidence of p16⫹ OPC is seen in all men regard-
less of race.50 HPV-mediated cancers most commonly arise
in the lymphatic tissue of the palatine and lingual tonsils,
and usually involve the upper and mid jugular lymph nodes
(Fig 8 and Table 7).49 Overall, p16⫹ OPC carries a better
prognosis with increased survival rates compared with its
p16⫺ counterpart.49
Interestingly, immunohistochemistry for p16 overex-
pression is used as a surrogate for HPV-mediated OPC.2,7
The 8th Edition states, “Direct detection of HPV is not used
as a defining factor due to its difficulty in universal avail-
ability, cost, and failure to stratify survival as well as p16⫹
overexpression.”2,7 It is important to note that HPV⫹ OPC
without p16⫹ is not considered HPV mediated. Further-
more, these cancers may stain for p16 but ultimately not
meet criteria to be considered p16⫹ (termed p16⫺).2,7
There is somewhat of an inverse relationship between p16
versus p53 and the retinoblastoma protein; that is, as HPV
oncoproteins degrade p53 and retinoblastoma protein, then
expression of p16 is upregulated and becomes the driver of
the carcinoma.2 Conversely, if p16 is not overexpressed,
then it is likely not the driver for the OPC; p53 mutations
may remain the driver in these lesions, which leads to a
more-aggressive and harder-to-treat carcinoma. This may
explain why HPV status alone fails to stratify survival as
well as p16 positivity. Subsequently, OPCs that stain for
p16 but do not meet criteria for p16 overexpression are
staged and treated according to the p16⫺ OPC TNM stag-
ing system.
The TNM staging system for p16⫹ OPC is entirely new
in the 8th Edition. When combined with the corresponding
prognostic staging group, this may result in significant
downstaging of p16⫹ OPC relative to p16⫺ OPC (Table
5), which reflects the differences in molecular mechanisms
and outcomes of these cancers. It is important to recognize
that, although ENE is not used in the p16⫹ OPC TNM
staging system, ENE does affect prognosis and may have
treatment implications.54-56 Compared with p16⫹ OPC
without ENE, those with ENE have decreased overall
survival.54 Thus, as discussed in the next section, it is still
important to describe ENE in the radiology report and at
the tumor board so that the appropriate prognosis is
provided to the patient and the best treatment algorithm
may be pursued. Again, there is a category T0 descrip-
tion, defined as unknown primary in the setting of a
p16⫹ cervical lymph node. This scenario results in stag-
ing according to the p16⫹ OPC chapter versus staging
according to the unknown primary tumor chapter, as
previously discussed.
HPC
HPC is relatively uncommon and carries the worst progno-
sis of all head and neck squamous cell cancers.51,57,58 Sim-
ilar to p16⫺ OPC, it is highly associated with tobacco use
and, specifically, smoking exposure.51,57,58 HPC is more
common in men.57 At this time, it is unclear how HPV
influences HPC.59 Thus, even though p16 overexpression is
found in approximately 16% of HPC, p16 positivity cur-
rently plays no role in HPC staging.51,59
HPC is most commonly located in the piriform si-
nus.57,58 Other relatively common primary sites include the
posterior pharyngeal wall and the postcricoid region.57,58
HPC often presents at an advanced stage in a patient with a
neck mass, weight loss, and a change in voice quality, pos-
sibly with dysphagia or odynophagia due to the tumor nar-
rowing the pharyngoesophageal junction.57 HPC tumors in
the piriform sinus tend to present with referred otalgia;
therefore, HPC should be considered when evaluating an
adult patient without a clear cause for primary otalgia.57
Again, there have been a number of changes to the Oro-
pharynx (p16⫺) and Hypopharynx chapter, which are
summarized in Table 5. Similar to both unknown primary
and p16⫺ OPC, the addition of ENE in the 8th Edition for
HPC is due to its grim prognosis. HPC with ENE results in

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Table 5B: Comparison between 7th edition OPC and 8th edition p16ⴙ and p16ⴚ OPC TNM clinical staging systems
Category 7th Edition OPC 8th Edition p16⫺ OPC *NEW* 8th Edition p16⫹ OPC
T Primary tumor Primary tumor Primary tumor

TX Primary tumor cannot be assessed Primary tumor cannot be assessed No TX

T0 No evidence of primary tumor
Tis Carcinoma in situ
T1 Tumor ⱕ 2 cm in greatest dimension
T2 Tumor ⬎ 2 cm but not ⬎ 4 cm in greatest
dimension
T3 Tumor ⬎ 4 cm in greatest dimension OR
extension to lingual surface of epiglottis
T4 Divided into T4a and T4b
T4a Tumor invades the larynx, extrinsic
muscles of the tongue, medial pterygoid
muscle, hard palate, or mandible
T4b Tumor invades the lateral pterygoid
muscle, pterygoid plates, lateral
nasopharynx, skull base, or encases
carotid artery
N Regional lymph nodes
Now staged according to the unknown
primary chapter
Carcinoma in situ
Tumor ⱕ 2 cm in greatest dimension
Tumor ⬎ 2 cm but not ⬎ 4 cm in greatest
dimension
Tumor ⬎ 4 cm in greatest dimension OR
extension to lingual surface of epiglottis
Divided into T4a and T4b
Tumor invades the larynx, extrinsic
muscles of the tongue, medial pterygoid
muscle, hard palate, or mandible
Tumor invades the lateral pterygoid
muscle, pterygoid plates, lateral
nasopharynx, skull base, or encases
carotid artery
Regional lymph nodes
No primary tumor identified, but p16ⴙ
cervical node involvement
No Tis
Tumor ⱕ 2 cm in greatest dimension
Tumor ⬎ 2 cm but not ⬎ 4 cm in greatest
dimension
Tumor ⬎ 4 cm in greatest dimension OR
extension to the lingual surface of the
epiglottis
Moderately advanced local disease; tumor
invades the larynx, extrinsic muscles of
the tongue, medial pterygoid muscle,
hard palate, or mandible or beyond
No T4a
No T4b
Regional lymph nodes

NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in a single ipsilateral lymph
node, ⱕ3 cm in greatest dimension
N2 Divided into N2a, N2b, and N2c
N2a Metastasis in a single ipsilateral lymph
node, ⬎3 cm but ⬍ 6 cm
N2b Metastasis in multiple ipsilateral lymph
nodes, none ⬎ 6 cm in greatest
dimension
N2c Metastasis in bilateral or contralateral
lymph nodes, none ⬎ 6 cm in greatest
dimension
N3 Metastasis in a lymph node ⬎ 6 cm in
greatest dimension
Note:—Adapted from Refs 7 and 51.
Regional lymph nodes cannot be assessed Regional lymph nodes cannot be assessed
No regional lymph node metastasis No regional lymph node metastasis
Metastasis in a single ipsilateral lymph Metastasis in ⱖ 1 ipsilateral lymph nodes,
node, ⱕ3 cm in greatest dimension and none ⬎ 6 cm in greatest dimension
ENE(ⴚ)
Divided into N2a, N2b, and N2c Bilateral or contralateral lymph nodes,
none ⬎ 6 cm in greatest dimension
Metastasis in a single ipsilateral lymph No N2a
node, ⬎3 cm but ⬍6 cm in greatest
dimension and ENE(ⴚ)
Metastasis in multiple ipsilateral lymph No N2b
nodes, none ⬎ 6 cm in greatest
dimension and ENE(ⴚ)
Metastasis in bilateral or contralateral No N2c
lymph nodes, none ⬎ 6 cm in greatest
dimension and ENE(ⴚ)
N3a: Metastasis in a lymph node, ⬎6 cm in Lymph node(s) ⬎ 6 cm in greatest
greatest dimension and ENE(ⴚ) dimension
N3b: ENE(ⴙ)

category N3b, which corresponds to stage IVB and is only
upstaged by distant metastasis.
LYMPH NODES AND ENE
There have been a number of CT, MR imaging, and ultra-
sound studies that have attempted to identify which imag-
ing features are most accurate at detecting cervical nodal
metastasis.9,60-63 Many of these studies have developed
their own size criteria and/or plane of measurement for
determining if a lymph node should be considered patho-
logic on imaging; unfortunately, there is no consensus on
size limitations for cervical lymph nodes.9,61-63 This is, in
part, because cervical lymph nodes may be enlarged due to
a reactive cause or metastasis. Furthermore, a normal-size

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Table 5C: 8th edition p16ⴙ OPC and p16ⴚ OPC and hypopharyngeal carcinoma prognostic stage groups
Category 7th Edition HPC 8th Edition HPC
T Primary tumor Primary tumor

TX Primary tumor cannot be assessed Primary tumor cannot be assessed

T0 No evidence of primary tumor Now staged according to unknown primary chapter
Tis Carcinoma in situ Carcinoma in situ
T1 Tumor limited to one subsite of hypopharynx and ⱕ 2 cm in Tumor limited to one subset of the hypopharynx and ⱕ 2 cm
greatest dimension in greatest dimension
T2 Tumor invades ⬎ 1 subsite of hypopharynx or an adjacent site, Tumor invades ⬎ 1 subsite of hypopharynx or an adjacent site,
or measures ⬎ 2 cm but ⬍ 4 cm in greatest dimension and or measures ⬎ 2 cm but ⬍ 4 cm in greatest dimension and
without fixation of hemilarynx without fixation of hemilarynx
T3 Tumor measures ⬎ 4 cm in greatest dimension or with fixation Tumor measures ⬎ 4 cm in greatest dimension or with
of hemilarynx or extension to esophagus fixation of hemilarynx or extension to esophageal mucosa
T4a Moderately advanced local disease: Tumor invades the thyroid/ Moderately advanced local disease: Tumor invades the
cricoid cartilage, hyoid bone, thyroid gland, or central thyroid/cricoid cartilage, hyoid bone, thyroid gland,
compartment soft tissue esophageal muscle, or central compartment soft tissue
T4b Very advanced local disease: Tumor invades the prevertebral Very advanced local disease: Tumor invades the prevertebral
fascia, encases carotid artery, or involves mediastinal fascia, encases carotid artery, or involves mediastinal
structures structures
N Regional lymph nodes Regional lymph nodes

NX Regional lymph nodes cannot be assessed Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis No regional lymph node metastasis
N1 Metastasis in a single ipsilateral lymph node, ⱕ 3 cm in greatest Metastasis in a single ipsilateral lymph node, ⱕ 3 cm in
dimension greatest dimension and ENE(ⴚ)
N2a Metastasis in a single ipsilateral lymph node, ⬎3 cm but ⬍ 6 cm Metastasis in a single ipsilateral lymph node, ⬎3cm but ⬍ 6
cm in greatest dimension and ENE(ⴚ)
N2b Metastasis in multiple ipsilateral lymph nodes, none ⬎ 6 cm in Metastasis in multiple ipsilateral lymph nodes, none ⬎ 6 cm in
greatest dimension greatest dimension and ENE(ⴚ)
N2c Metastasis in bilateral or contralateral lymph nodes, none ⬎ 6 Metastasis in bilateral or contralateral lymph nodes, none ⬎ 6
cm in greatest dimension cm in greatest dimension and ENE(ⴚ)
N3 Metastasis in a lymph node ⬎ 6 cm in greatest dimension N3a: Metastasis in a single lymph node, ⬎ 6 cm in greatest
dimension and ENE(ⴚ)
N3b: ENE(ⴙ)
Note:—Adapted from Refs 7 and 51.

Table 5D: 8th edition chapter 10. HPV-mediated (p16ⴙ) OPC Table 5E: 8th edition chapter 11. Oropharynx (p16ⴚ) and hypopharynx
prognostic stage groups prognostic stage groups
T0 T1 T2 T3 T4 Tis T1 T2 T3 T4a T4b

M0 M0
N0 I I II III N0 0 I II III IVA IVB
N1 I I I II III N1 III III III IVA IVB
N2 II II II II III N2 IVA IVA IVA IVA IVB
N3 III III III III III N3 IVB IVB IVB IVB IVB
M1 M1
Any N IV IV IV IV IV Any N IVC IVC IVC IVC IVC
Note:—Adapted from Ref 7. Note:—Adapted from Ref 51.
M0 ⫽ no distant metastasis. M0 ⫽ no distant metastasis.
M1 ⫽ distant metastasis. M1 ⫽ distant metastasis.

lymph node may actually contain metastasis. In general, ment, indistinct borders, and central necrosis.9,10,12,60-63
radiologic features of malignant lymphadenopathy include Despite there being no consensus on abnormal lymph node
increased size, abnormal morphology, increased enhance- size, it is important to note that, with regard to the TNM

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Fig 6. Oropharyngeal carcinoma primary sites. A, Midsagittal T1, illus-
trating common primary sites: base of tongue (dotted red line), soft pal-
ate (dotted green line), and posterior pharyngeal wall (dotted pink line).
B, Axial T1 image, demonstrating the tonsillar fossae; the most common
location for oropharyngeal carcinoma.
Fig 7. A 51-year-old man presented with dysphagia. High-resolution con-
trast-enhanced (A) axial and (B) midsagittal CT, demonstrating a 5-cm
oropharyngeal carcinoma (red arrows) at the base of the tongue and
involves the lingual surface of the epiglottis (teal arrow). There is no
regional lymphadenopathy or distant metastasis. This tumor was a p16ⴚ
oropharyngeal carcinoma.
staging system, cervical lymph nodes should be measured in
the greatest dimension and not simply the short-axis dimen-
sion. The 8th Edition directly states, “Regional nodal status
(greatest dimension in any direction, laterality, location,
and lowest extent of nodal involvement) should be as-
sessed; measurement of the maximal diameter of nodal
disease should not be confined to the axial radiologic
plane only.” This illustrates the importance of thin-sec-
tion helical acquisition with multiple reformatted planes.
Even though there is no consensus on a cutoff size for
determining a pathologic lymph node, ENE is more likely
in larger nodes; for example, ENE occurs in 23% of
lymph nodes ⬍10 mm in greatest dimension versus 53%
and 74% for lymph nodes that measure 20 –30 mm and
⬎30 mm, respectively.9
Again, this review article was about clinical stage classi-
fication, and when ENE was discussed above, it referred to
clinically overt ENE (cENE) and/or radiologically overt
ENE (rENE). cENE is defined by physical examination find-
ings that include invasion of adjacent skin and musculature
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Table 6: Comparison of 7th edition versus 8th edition clinical staging
systems for the oropharyngeal carcinoma that is depicted in Figure 7
7th Edition - Stage III
T3 Tumor ⬎ 4 cm in greatest dimension OR extension to
lingual surface of epiglottis
N0 No regional lymph node metastasis
M0 No distant metastasis
8th Edition - Stage III for p16⫺
T3 Tumor ⬎ 4 cm in greatest dimension OR extension to
lingual surface of epiglottis
N0 No regional lymph node metastasis
M0 No distant metastasis
NEW 8th Edition - Stage II for p16⫹
T3 Tumor ⬎ 4 cm in greatest dimension OR extension to
lingual surface of epiglottis
N0 No regional lymph node metastasis
M0 No distant metastasis
Note:—Adapted from Ref 7, 51.
In the 7th edition, the OPC in Figure 7 would have been stage III; however, in the 8th
edition this tumor represents stage III if p16⫺ and stage II if p16⫹.
as well as signs or symptoms from involvement of adjacent
cranial, sympathetic, or parasympathetic nerves.2 rENE is
defined by the 8th Edition as strong radiologic evidence of
expected cENE, such as tethering of adjacent structures,
irregularity of the nodal rim, or overt infiltration into the
adjacent tissues (Fig 9).9,12 In fact, lymph nodes that dem-
onstrate irregular borders and surrounding fat stranding
are associated with pathologically proved ENE (pENE),
regardless of lymph node size.9,10,12 In 2013, Lodder et
al12 found that the presence of infiltration into adjacent
tissues when using postcontrast high-field strength (3.0 T)
MR imaging was 100% specific and 50% sensitive for ENE.
In 2015, Aiken et al10 reported that the best radiologic predic-
tor of pENE is central nodal necrosis, even in the absence of
irregular borders or fat stranding (Fig 10). Similar to Lodder et
al,12 they also demonstrated high specificity and moderate
sensitivity; central nodal necrosis was 93% specific and 66%
sensitive for predicting pENE, and perinodal stranding was
89% specific and 63% sensitive.10
Other studies also assessed central nodal necrosis as a
predictor of ENE and repeatedly demonstrated high speci-
ficity and at least moderate sensitivity.10,11,64 Thus, from a
probability standpoint, when a radiologist identifies rENE,
then pENE is present; however, if rENE is not present on
imaging, then pENE may or may not be present. So, the
interpreting radiologist who does not see rENE should not
be surprised when pathology returns as positive for pENE
given the low-to-moderate sensitivity of rENE. Again,
rENE is defined by the 8th Edition as strong radiologic
evidence of cENE and thus pENE. Moreover, due to the
highly specific nature of rENE, if the initial clinical eval-
uation was negative for cENE but rENE was identified on
subsequent imaging, then the presence of rENE should
prompt clinical reevaluation for corroborative evidence
Fig 8. A 45-year-old man with a palpable neck mass. A, High-resolution axial T2 fat saturation image demonstrates a 1.2-cm oropharyngeal carcinoma
(red arrow) centered within the right palatine tonsil. B, High-resolution contrast-enhanced axial T1 fat saturation image, revealing involvement of the
ipsilateral medial pterygoid muscle (green arrow). C, Coronal T2 image with a single ipsilateral 4.5-cm cystic regional lymph node (orange arrows).
There is no distant metastasis.

Table 7: Comparison of 7th edition versus 8th edition clinical staging systems for the oropharyngeal carcinoma that is depicted in Figure 8

7th Edition - Stage IVA

T4a Tumor invades the larynx, extrinsic muscles of the tongue, medial pterygoid muscle, hard palate, or mandible
N2a Metastasis in a single ipsilateral lymph node, ⬎3 cm but ⬍ 6 cm
M0 No distant metastasis
8th Edition - Stage IVA for p16⫺

T4a Tumor invades the larynx, extrinsic muscles of the tongue, medial pterygoid muscle, hard palate, or mandible
N2a Metastasis in a single ipsilateral lymph node, ⬎3 cm but ⬍ 6 cm in greatest dimension and ENE(ⴚ)
M0 No distant metastasis
NEW 8th Edition - Stage III for p16⫹

T4 Tumor invades the larynx, extrinsic muscles of the tongue, medial pterygoid muscle, hard palate, or mandible or beyond
N1 Metastasis in ⱖ1 ipsilateral lymph nodes, none ⬎ 6 cm in greatest dimension
M0 No distant metastasis
ENE ⫽ extranodal extension.
ENE(⫹) ⫽ positive for ENE.
ENE(⫺) ⫽ negative for ENE.
In the 7th edition, the OPC in Figure 8 would have been stage IVA; however, in the 8th edition this tumor represents stage IVA if p16⫺ and stage III if p16⫹; this tumor
was a p16⫹ OPC.

Fig 9. Radiologically overt ENE in a 64-year-old man with p16ⴚ oropharyngeal carcinoma. A, Contrast-enhanced axial and (B) coronal CT of the neck
with a level II necrotic lymph node conglomerate, demonstrating indistinct margins and infiltration of surrounding tissues. C, Photomicrograph of ENE.
Black asterisk demonstrates islands of tumor cells replacing normal lymph node architecture. The black arrows are displaying keratin pearls consistent
with well-differentiated squamous cell carcinoma. Red arrow ⴝ lymph node capsule. Red arrowhead ⴝ region of ENE of tumor through the capsule.
Stain: haemotoxylin and eosin (magnification x100).

of cENE. Likewise, if rENE is present but pathology
results are negative for pENE, then this should be viewed
as discordant.
A detailed description of pENE is beyond the scope of
this review; however, histopathologic examination is
considered the criterion standard for the diagnosis of
ENE and is defined as tumor that extends beyond the
lymph node capsule.2,51 The 8th Edition further divides
pENE into either microscopic pENE or macroscopic
pENE. Microscopic pENE is defined as tumor extension

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Fig 10. Coronal contrast-enhanced neck CT in a 37-year-old man, with a
left level II cervical lymph node, demonstrating central necrosis in the
setting of a p16ⴙ oropharyngeal carcinoma. In addition, the periphery of
this lymph node demonstrates a lobulated border. Central nodal necrosis
is the best radiologic predictor of ENE.
beyond the lymph node capsule but of ⱕ2 mm, whereas
macroscopic pENE represents tumor extension of ⬎2
mm beyond the lymph node capsule.51
SUMMARY
Several important changes have been made to the 8th Edi-
tion relevant to head and neck imagers. First, there is an
entirely new staging system for cervical nodal metastasis in
the setting of an occult primary tumor. Clinicians no longer
need to guess at the likely primary site as was the case with
the 7th Edition. Important clinical staging features for this
unknown primary chapter include the category N descrip-
tor ENE and the inclusion of viral status in cervical nodal
metastasis. That is, if a cervical nodal metastasis is EBV⫹ or
p16⫹, then it should be staged according to the Nasophar-
ynx chapter or p16⫹ OPC chapter, respectively.
For NPC, major 8th Edition changes include the down-
staging of “invasion of the pterygoid or prevertebral mus-
cles” from category T4 to T2 and the addition of the cate-
gory T0, which represents an unknown primary tumor with
EBV⫹ cervical lymph node metastasis.
A p16⫹ OPC is now recognized as a separate entity
from p16⫺ OPC and, accordingly, gets its own chapter in
the 8th Edition, which reflects its unique staging system
that considers the overall improved prognosis of p16⫹
OPC relative to p16⫺ OPC. As with the NPC chapter, we
108 兩 Neurographics 2019 March/April;9(2):96 –110; www.neurographics.org
have the addition of the category T0, which represents an
unknown primary tumor with p16⫹ cervical lymph node
metastasis.
Similar to the unknown primary, p16⫺ OPC and HPC
now include ENE as a new category N descriptor.
As discussed throughout this review, ENE is a new cate-
gory N descriptor for the unknown primary tumor chapter
as well as the p16⫺ OPC and HPC chapter. It represents a
universally dismal prognosis and constitutes category N3b,
which corresponds to stage IVB disease. The only way to
upstage ENE to stage IVC is with the presence of distant
metastasis. Radiologists should be aware that, although
ENE has no role in the 8th Edition TNM staging system for
p16⫹ OPC or NPC, it also portends a poor prognosis for
these entities and may have treatment implications.30,54,55
CONCLUSIONS
Now more than ever, staging, prognosis, and prospective
treatments rendered for patients afflicted with these cancers
rely on a highly informed and clinically competent radiolo-
gist. Familiarity and appropriate application of the con-
cepts summarized in this review will have a profoundly
positive impact on our referring providers and the patients
we serve.
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2. Lydiatt WM, Patel SG, Ridge JA, et al. Staging head and neck
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