ARTICLE IN PRESS

PET-CT for Staging and Detection of

Recurrence of Head and Neck Cancer
Wai Lup Wong, BA (Hons), LLM, FRCR, FRCP*,†

FDG PET-CT is one the main investigations for squamous cell (Sq) head and neck (H&N)
cancer patients. FDG PET-CT has a key role for the staging of patients with T4 cancer of the
hypopharynx and nasopharynx and patients with N3 nodal disease. It is effective in detect-
ing recurrent disease accurately. In addition, it has an emerging role in the surveillance of
Sq H&N cancer survivors. In patients with advanced neck nodal disease treated with che-
moradiotherapy, there is compelling evidence that patients with no FDG uptake in the neck
12 weeks following completion of treatment do not require neck dissection. There is consid-
erable interest in using FDG PET-CT for develop more effective clinical pathways for the
surveillance of Sq H&N cancer. Currently, the detection rate of recurrence in patients who
attend regular clinical follow-up is poor, less than 1% in asymptomatic patients. FDG PET-
CT may enable survivors to be stratified into groups based on the likelihood of having recur-
rent disease. Optimal surveillance pathways can be developed, reserving most intense
imaging regimes and most frequent follow-up for survivors at high risk of recurrence. FDG
PET CT is sometimes considered for patients with non Sq H&N cancer. If used in this con-
text, a baseline FDG PET-CT should be done to ensure that the tumour is avid. Most H&N
malignant tumours are avid. However, salivary gland cancers, and tumours with muco-
epidermoid, adenoid cystic and clear cell histology show paucity of FDG avidity, especially
when they recur. In addition, peri-neural invasion cannot be detected reliably with FDG
PET-CT.
Semin Nucl Med 00:1-13 Crown Copyright © 2020 Published by Elsevier Inc. All rights
reserved.

Background squamous cell (Sq) H&N cancer. FDG PET-CT is indicated

for the staging and for the detection of residual and recurrent

T he value of positron emission tomography (PET) for

head and neck (H&N) cancer was recognised very early
in the history of PET. H&N cancer was identified as one of
the first clinical indications for PET.1,2 The advent PET-CT
saw an acceleration of the clinical utility of this technique.
FDG PET-CT is now a key diagnostic tool for H&N cancer.
It is an essential examination for the detection of the primary
site in patients who present with a malignant neck lymph
node and no evidence of cancer on the upper aerodigestive
tract mucosa.4-7 In addition, FDG PET-CT has been estab-
lished as one of the main investigations for patients with
disease in this group. It also has emerging role in the surveil-
lance of Sq H&N cancer survivors. PET-CT has led to more
accurate diagnoses and it has contributed to improved out-
comes in H&N cancer patients.3 The article will focus partic-
ularly on the impact that recent evidence has had on use
FDG PET-CT for Sq H&N cancer. In addition, a short com-
mentary will be provided on the role of FDG PET-CT for
non-squamous cell cancers of the H&N and on some of the
pitfalls when using FDG PET-CT for H&N cancer.

*Consultant Radiologist (Nuclear Medicine) Mount Vernon Hospital, North- Staging

wood, UK. Sq H&N cancers are staged according to the internationally
y
PET-CT Clinical Lead Strickland Scanner Centre, Northwood, UK.
Address reprint requests to Wai Lup Wong, BA (Hons), LLM, FRCR, FRCP,
recognised TNM system.8 Computed tomography (CT) and
Consultant Radiologist (Nuclear Medicine) Mount Vernon Hospital, magnetic resonance (MR) imaging remain the mainstay for
Northwood, UK. E-mail: wailup.wong@nhs.net the T (tumour) staging of H&N malignant tumours.8,9

https://doi.org/10.1053/j.semnuclmed.2020.09.004 1
0001-2998/Crown Copyright © 2020 Published by Elsevier Inc. All rights reserved.
 ARTICLE IN PRESS
2 W.L. Wong
Ultrasound scanning (USS) with fine needle aspiration
cytology (FNAC) together with CT and MR for N (nodal)
staging.8,10 FDG PET-CT is reserved for the occasional
situation when further imaging is required after usual
investigations.
The main role of FDG PET-CT in Sq H&N cancer patients
is in M (metastatic disease) staging, utilizing its ability to
detect distant metastases. However, the presence of distant
metastases is generally uncommon in upper aerodigestive
tract cancers. The National Head and Neck Cancer Data for
Head and Neck Oncology (DAHNO) reports of 2013 and
2014, stated that distant metastases were present in 548 of
18,968 patients with upper aerodigestive tract cancer, equat-
ing to an overall prevalence of 3%. However, further analysis
shows that the risk of distant metastases was much higher in
certain sub-groups. For example, in hypopharyngeal cancer,
96 of 1,118 patients had metastases, equating to a prevalence
of 9%.7,11,12 Drawing from this and other evidence, the cur-
rent NICE guidance recommends offering systemic staging,
and specifically FDG PET-CT, to patients with T4 cancer of
the hypopharynx and nasopharynx and to patients with N3
cancer of the upper aerodigestive tract.7 Systemic staging was
found to be not cost-effective in all patients with Sq H&N
cancers, as the benefits afforded were too small to justify the
additional costs.
The ability of FDG PET-CT to detect synchronous cancers
is often forwarded as a justification for extending the use of
PET-CT for staging Sq H&N cancer to beyond advanced
loco-regional disease. This deserves some consideration given
that chronic exposure to tobacco smoke and excessive alco-
hol consumption, which are causal factors of Sq H&N can-
cer, are associated with many other malignant solid tumours,
including those arising on the thoracic oesophagus, stomach,
pancreas, bladder, kidney, liver, colon, rectum, breast and
cervix.13,14 However, in Sq H&N cancer patients, the major-
ity of synchronous cancers arise from the H&N. Synchro-
nous tumours outside the H&N are very rare and only
demonstrated in around 1%. These occur mainly in the
chest, with 66% being carcinomas of bronchus, and the
remainder mostly oesophageal carcinomas.15,16 This obser-
vation begs the as yet unanswered question as to the extent
to which FDG PET-CT improves the detection of synchro-
nous cancers beyond well performed state of the art breath-
hold chest CT and H&N MR.
With diagnostic imaging there is always a trade-off
between detecting relevant disease and detecting incidental
lesions that are of no clinical relevance. Specifically, with
staging investigations, the decision as to who should be sys-
temically imaged is made on balancing the probability of
detecting metastases against the cost of detection. In patients
with a low pre-test probability of having metastases, imaging
can trigger further investigations for lesions which will even-
tually turn out to be benign. The unnecessary investigations
can erode patient experience and it can also cause delays in
treatment17,18 This issue was highlighted by a study that
showed that the investigation of lung lesions raised by PET-
CT led to unnecessary delays in starting treatment for a sig-
nificant number of patients.18 A similar situation may arise
when PET-CT detects unexpected FDG avid lesions in the
colon. Some of these lesions will be pre-malignant or malig-
nant but a significant number will be due to benign pathol-
ogy including benign polyps and diverticulitis. The
acceptable level of unwarranted investigations required to
detect one patient with metastases involve decisions which
extend beyond the science of imaging. The tipping point
varies between guideline making groups, and this contributes
to the observation that different recommendations can be
made using similar evidence bases.19
A further role of FDG PET-CT in Sq H&N cancer patients,
in common with other cancers, and irrespective of T and N
stage, is the assessment of indeterminate lesions on usual
assessment including those in lung, liver and adrenal glands.
FDG PET-CT will improve characterisation and can change
the treatment plan.20
Detection of Recurrence
There is an extensive evidence base to show that FDG PET is
superior to conventional imaging for distinguishing treat-
ment sequelae from recurrence.21 There are limited data on
FDG PET-CT in this area. However, that does not diminish
the value of FDG PET-CT. It is generally recognised that
FDG PET-CT is at least as accurate as FDG PET and that
includes in the assessment of Sq H&N cancer.22 In a clinical
setting, for the individual patient, the question that is asked
is the extent of benefit afforded by diagnosing recurrence.
Or, in other words, the impact establishing the diagnosis
would have for the individual (Fig. 1).
Surveillance
Wide differences are seen between institutions and countries
on the management of advanced nodal (N2-N3) disease in
Sq H&N cancer patients treated with primary chemoradio-
therapy (CRT).23 By way of example, many centres in the US
adopt image-guided, response-based strategies. This is in
contrast to European practice.23 In the UK, in a national
audit, up to 48% of oropharyngeal cancer patients were
found to have neck dissection as their first treatment.24 In
France, 35% of H&N clinicians surveyed reported that they
commonly or routinely performing neck dissection before
CRT.25 One of the reasons for the variation is that up to
recently, there has been a lack of compelling evidence to sup-
port using image guided response-based strategies as an alter-
native neck dissection.
PET-CT research has provided this evidence. Two meta-
analyses showed FDG PET and PET-CT had high negative
predictive values (NPV) of between 94% and 96% and posi-
tive predictive values (PPV) of approximately 50% for detect-
ing disease following CRT. However, most studies in the
literature were small and from single institutions.26,27 The
PETNECK study built on this and provided strong evidence
to support a change in practice.28 PETNECK was a prospec-
tive randomised controlled study.28 Around 564 patients
 ARTICLE IN PRESS
PET-CT for Staging and Detection of Recurrence of Head and Neck Cancer 3

Figure 1 There is intense FDG uptake in the right level IIA due to recurrence in the post-treatment neck (arrow). There
is decreased uptake in the right side of the tongue due to atrophy and fat replacement following radiotherapy (hollow
arrows).

with advanced neck nodal disease (N2 or N3) were random-
ized into either a planned neck dissection arm or a PET-CT
active surveillance arm. In the surveillance arm, FDG PET-
CT was performed 12 weeks after completion of CRT.
Patients with incomplete responses and equivocal responses
on FDG PET-CT scanning received a neck dissection. Intense
FDG uptake with or without enlarged lymph nodes were
classified as an incomplete response. Mild or no FDG uptake
in enlarged lymph nodes and mild uptake in normal sized
lymph nodes were classified as an equivocal response
(Fig. 2). Overall survival was similar in both arms of the
study. However, only 19% of patients had a neck dissection
in the FDG PET-CT arm, with less complications and the
same overall quality of life. The active surveillance FDG PET-
CT arm was significantly more cost-effective than the
planned neck dissection arm.

Figure 2 Appearance of FDG PET-CT which require neck dissection on the PETNECK study. (A) FDG PET-CT shows abnormal lymph nodes
on CT, but no increased FDG uptake. (B) FDG PET-CT shows normal lymph nodes on CT with FDG uptake which is abnormal, that is, higher
than that of FDG uptake in cerebellum (definitely abnormal) and FDG PET-CT shows normal lymph nodes on CT with FDG uptake which is
similar to FDG uptake in adjacent veins (equivocal).
 ARTICLE IN PRESS
4 W.L. Wong

Figure 2 (Continued)

There remain unanswered questions with regard imaging is unclear. It has been observed that HPV+ lymph nodes may
of the neck following non-surgical primary treatment of the take longer to involute completely; and therefore, enlarged
neck. First, the significance of enlarged human papilloma lymph nodes with no FDG uptake at 12 weeks post-chemo-
virus positive (HPV+) lymph nodes which are not FDG avid therapy and CRT may not contain disease.29 In addition to

Figure 3 Tuberculosis. A 33-year-old man with TB and HIV. FDG PET-CT shows intensely avid enlarged lymph nodes
in the neck, chest and abdomen. Cervical tuberculosis is one of the causes of extrapulmonary tuberculosis, and often
observed in individuals who are immunocompromised. Courtesy of Professor Mike Sathekge.
 ARTICLE IN PRESS
PET-CT for Staging and Detection of Recurrence of Head and Neck Cancer 5

Figure 4 Sarcoidosis. (A-C) Diffuse increased FDG in both submandibular glands due to infiltration with sarcoidosis.
sm, submandibular glands. (D-F) FDG uptake in normal sized lymph nodes in the neck and within the chest in the
right para-trachea, aorto-pulmonary window, and right pulmonary hilum due to involvement with sarcoid.

Figure 5 Paget’s disease of bone in the right hemipelvis (arrow). There is increased FDG uptake associated with CT find-
ings classical for the condition: Cortical thickening, osseous expansion, osteolysis, and trabecular coarsening extending
from a joint surface (the acetabular joint in this instance).
 ARTICLE IN PRESS
6 W.L. Wong

Table 1 FDG Uptake Due to Treatment Sequelae (A) Post-Surgery (B) Post-Radiotherapy
Post-surgery Comments

Chylous leak Related to recent neck dissection

An intensely FDG avid soft tissue mass in the left supraclavicular fossa around a surgical
clip due to a chylous leak following neck dissection (Fig. 6).
Granuloma  Due to surgical sutures
 Due to Teflon injection for vocal cord paresis
Teflon granuloma in the left vocal cord can have intense FDG uptake (hollow arrow) (Fig. 7).
Osteonecrosis Most commonly seen in the mandible
The challenge is distinguishing FDG uptake between recurrent disease and osteonecrosis
(Fig. 8).
Post-tonsillectomy Surveillance FDG PET-CT in a H&N cancer survivor. Results in asymmetrical tonsillar
uptake (Fig. 9).
Around trachea-ostomy Recurrence: FDG PET-CT shows SqCC recurrence on the posterior pharyngeal wall (red
arrows) and FDG uptake around the tracheostomy (Fig. 10).
Around gastrostomy FDG PET-CT shows SqCC recurrence in the floor of mouth (white arrow) and posterior
pharyngeal wall and a bone metastasis. There is also FDG uptake around the gastrostomy
site (Fig. 11).
1(A)

Post-radiotherapy Comments

Radiation myelitis
Radiation osteonecrosis
Post-radiation pneumonitis
Post-radiation spondylodiscitis
1 (B)
Post-radiation myelitis. (A) Diffuse FDG uptake in the cervical cord due to diffuse radiation
myelitis (B) Focal FDG uptake in the cervical cord due to focal radiation myelitis (Fig. 12).
A late sequelae of RT seen in laryngeal cartilage.
Laryngeal cartilage necrosis, following radiotherapy for laryngeal cancer with intense FDG
uptake in the cricoid cartilage (Fig. 13).
Usually seen at the lung apices, can be focal.

this, reports show that HPV+ residual lymph nodes that are
not FDG avid have low recurrence rates.30,31 In one study,
120 consecutive patients who achieved a complete response
at the primary site after definitive RT with or without concur-
rent systemic treatment underwent FDG PET with diagnostic
CT 12 weeks after completion of treatment. Those with
equivocal FDG PET had a repeat FDG PET 4 to 6 weeks later.
In the 41 patients with residual CT nodal abnormality which
showed no FDG uptake, none of them had subsequent iso-
lated nodal relapse during a follow-up period of over a

Figure 6 An intensely FDG avid soft tissue mass in the left supraclavicular fossa around a surgical clip due to a chylous
leak following neck dissection (arrow).
 ARTICLE IN PRESS
PET-CT for Staging and Detection of Recurrence of Head and Neck Cancer 7

Figure 7 A Teflon granuloma in the left vocal cord with intense FDG uptake (hollow arrow). The Teflon injection was
for palliative treatment for vocal paralysis due to a lung cancer in the left upper lobe and involvement of the left recur-
rent laryngeal nerve as a result of lymph nodal disease in the aortopulmonary window. a, prevertebral muscle; b, steno-
cleidomastoid muscle; c, lung cancer.

median of 28 months, with a range of 13 to 64 months.31
From the data, it is not unreasonable in patients with HPV+
disease and enlarged lymph nodes which are not FDG avid
after completion of treatment to consider close surveillance
with serial scanning. On the other hand, those with FDG
avid lymph nodes should continue to have a neck dissection,
especially if they have HPV- disease or have HPV+ disease
but are at a high risk for recurrence.
Second, the extent to which FDG PET-CT improves the
assessment of the neck following non-surgical primary treat-
ment over contrast-enhanced CT in unclear. A prospective
study by Moeller et al compared the diagnostic accuracy of
CT with FDG PET-CT in patients treated with primary RT
with or without chemotherapy. They found that FDG PET-CT
was only better than CT in 3 groups: HPV- disease and with a
high risk of recurrence, non-oropharyngeal primaries, and
those who have a history of tobacco use. No benefit was seen
in those who had a low risk of recurrence, namely non-smok-
ers, those with HPV+ disease or oropharyngeal primaries.32
On the other hand, one of the largest studies to date which
considered the value of FDG PET-CT in HPV+ oropharyngeal
cancer, showed that FDG PET-CT at 12 weeks following CRT
had a high negative predictive value (NPV) for predicting
loco-regional failure33 In addition, Pryor and colleagues dem-
onstrated that surveillance strategies which included FDG
PET-CT were more cost effective than those using CT alone,
regardless of the presence or absence of HPV disease .The
study also showed that combined strategies using CT followed
by FDG PET-CT in non-responders were only marginally
more cost effective than FDG PET-CT alone.34 As yet, inde-
pendent validation of CT scan-driven response systems or
comparison with PET-CT driven systems in multicenter,
randomised settings has not been published. As a final com-
ment, even if further studies show FDG PET-CT is of limited
value in HPV+ patients, it should perhaps be noted that in
many countries, HPV+ disease constitutes only a minority of
patients, and FDG PET-CT would still have an important role
in the majority of patients worldwide.
There is considerable interest in extending the role of FDG
PET-CT beyond the detection of Sq H&N cancer during the
immediate period following non-surgical treatment. This is
driven by the need to urgently develop more effective clinical

Figure 8 Osteonecrosis of the mandible following surgery with intense FDG uptake (arrow). The challenge is distin-
guishing between recurrent disease and osteonecrosis.
 ARTICLE IN PRESS
8 W.L. Wong

Figure 9 Surveillance FDG PET-CT in an H&N cancer survivor. Focal FDG uptake in the right oropharyngeal wall not
present on the left oropharyngeal wall (arrow). The asymmetrical FDG uptake is due to a previous left tonsillectomy.
The patient has developed a metachronous lung cancer (hollow arrow) and a metachronous malignant colonic polyp
(arrowhead).

pathways for the surveillance of Sq H&N cancer survivors as
currently the detection rate of recurrent disease from routine
clinical follow-up is poor. In a study of 1,039 consecutive
out-patient consultations, recurrence was found in 2 of
1,039 asymptomatic survivors. On the other hand, for those
who were symptomatic and requested an additional appoint-
ment, the detection rate rose to 58%.35 Survivors themselves
recognise the limitations of current pathways. In one study,
84% of survivors felt that their follow-up was too frequent
and 73% favoured a symptom-based appointment system.36
FDG PET-CT can potentially play an important role in
improving the surveillance pathways of Sq H&N survivors.
In a meta-analysis, FDG PET-CT showed a sensitivity 92%
(95% confidence interval (CI), 0.85-0.96) and a specificity of
91% (95% CI, 0.78-0.96), for detecting recurrence at 1 year
following completion of treatment. Albeit drawing largely
from small retrospective studies, it was noted that accuracy
was higher in those with no symptoms compared to those
who were symptomatic.37 Adding to the meta-analysis, a
study of 279 survivors showed that diagnostic accuracy of a
surveillance PET/CT scan after Sq H&N cancer improves
with time since treatment, and is very reliable after 1 year. In
the study of survivors primarily treated with radiotherapy
the proportion of inconclusive results declined from 26% to
8.4% and 0% after 0-3, 3-6 and 12-24 months post-treat-
ment respectively.38 One recent Australian study showed
that FDG PET-CT was cost-effective, when comparing an
FDG PET-CT surveillance policy with routine follow up,
with a saving of AUD$ 2606 per patient over 2 years and
AUD$ 5012 over 5 years.39
 ARTICLE IN PRESS
PET-CT for Staging and Detection of Recurrence of Head and Neck Cancer
FDG PET-CT for Non-Sq H&N
Cancer
There is limited evidenced guidance for the use of FDG PET-
CT here, beyond anecdotal reports, as these tumours are
extremely rare. Notwithstanding, FDG PET-CT is often done
prior to treatment and for several reasons. First, to demonstrate
that the tumour is FDG avid, if so, FDG PET-CT is used for
pre-treatment staging, and subsequently to detect residual/
recurrent disease. Most H&N malignant tumours are avid.
However, salivary gland cancers, and tumours with muco-epi-
dermoid, adenoid cystic and clear cell histology show paucity
of FDG avidity, especially when they recur. In addition, peri-
neural invasion cannot be detected reliably with FDG PET-CT.
Pitfalls
A comprehensive and full discourse on pitfalls is beyond the
scope of the chapter. The aim of this section is to highlight
Figure 10 FDG PET-CT shows SqCC recurrence on the posterior pharyngeal wall (red arrows) and FDG uptake around
the tracheostomy (black arrow).
9
some of the more often encountered pitfalls that can cause
confusion in the context of H&N cancer staging and detec-
tion of recurrence. First, granulomatous disease requires con-
sideration. The 2018 global report from the World Health
Organisation (WHO) reported an incidence of 10 million
cases of tuberculosis (TB) worldwide, and identified it as the
leading cause of death due to infectious disease. HIV disease
has contributed to the increase in incidence of TB as HIV
patients are particularly prone to TB. They are 20 to 30 times
more likely to develop TB compared with patient not
infected with HIV, who have only a 5%-10% chance of devel-
oping active TB in their lifetime.40 A study of 358 TB patients
across 6 countries, FDG PET-CT showed one extrapulmo-
nary site in 34% patients and more than one extra-pulmo-
nary site in 66%. Lymph nodes, the skeleton and pleura
were the common sites of disease.41 As TB granulomas are
intensely FDG avid, it comes as no surprise, that TB is the
grand mimicker of distant metastases.42 In the setting of TB,
FDG-PET has proven unable to differentiate malignancy
 ARTICLE IN PRESS
10 W.L. Wong

Figure 11 FDG PET-CT shows SqCC recurrence in the floor of mouth (white arrow) and posterior pharyngeal wall (red
arrow) and a bone metastasis (hollow arrow). There is also FDG uptake around the gastrostomy site (red arrowhead).

Figure 12 Post-radiation myelitis. (A) Diffuse FDG uptake in the cervical cord due to diffuse radiation myelitis (black arrows) (B) Focal FDG
uptake in the cervical cord due to focal radiation myelitis (black arrow).
 ARTICLE IN PRESS
PET-CT for Staging and Detection of Recurrence of Head and Neck Cancer
Figure 12 (Continued)
from TB in patients presenting with solitary pulmonary nod-
ules, including those suffering from HIV, and thus cannot be
used as a tool to reduce futile biopsy or thoracotomy in these
patients (Fig. 3).42
Like TB granulomas, sarcoid granulomas, need to be dis-
tinguished from metastases. The diagnosis of sarcoid is
raised by the distribution of FDG avid lymph nodes typical
for this condition, namely FDG avid lymph nodes in the
right para-trachea, both hila and sub-carina, combined
with a low pre-test probability of having chest nodal metas-
tases. Intra-pulmonary nodules however can cause more of
a diagnostic challenge, as can extra-nodal disease for exam-
ple in skeleton or liver. In addition to sarcoid, sarcoid-like
reactions are not uncommonly seen in H&N cancer
patients but this usually identified as it usually manifests as
avid lymph nodes in the chest in a distribution similar to
sarcoid (Fig. 4).43
Benign bone lesions can be FDG avid and need to be con-
sidered especially when there is a low likelihood of bone
metastases. Paget’s disease of bone particularly needs to be
Figure 13 Laryngeal cartilage necrosis, following radiotherapy for laryngeal cancer with intense FDG uptake in the cri-
coid cartilage (arrow).
11
distinguished from bone metastases (Fig. 5). Following treat-
ment, FDG uptake due to sequelae of interventions needs
careful consideration before making the diagnosis of recur-
rent disease.44-46 This is particularly important if the FDG
PET-CT findings are not consistent with the expected pattern
of disease (Table 1).
Conclusions
PET-CT has an established role to support its use for the stag-
ing and detection of residual and recurrent disease in Sq
H&N cancer patients. It also has emerging role in the surveil-
lance of Sq H&N cancer survivors. If FDG PET-CT is being
considered patients with non-squamous H&N cancer, as
part of their care, a pre-treatment FDG PET-CT should be
done to confirm that the tumour is FDG avid. There are pit-
falls that can occur when using FDG PET-CT for H&N can-
cer and a good understanding of these will improve greatly
the accuracy of FDG PET-CT as a diagnostic tool.
 ARTICLE IN PRESS
12
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