de Bree, Remco

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de Bree, R.

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The real additional value of FDG-PET in detecting the occult primary tumour in patients with cervical lymph node metastases of unknown primary tumour

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EDITORIAL
The real additional value of FDG-PET in detecting the occult
primary tumour in patients with cervical lymph node metastases
of unknown primary tumour
Remco de Bree
Published online: 9 September 2010
 The Author(s) 2010. This article is published with open access at Springerlink.com
Cervical lymph node metastases may be the first manifes-
tation of cancer. In some patients presenting with a cervical
lymph node metastasis, the primary tumour remains elusive
after extensive diagnostic work-up. In such cases, the
patient is classified as having a so-called unknown primary
tumour (UPT). The incidence of UPT ranges from 3 to 7%
of all head and neck cancers. The most commonly histo-
logical diagnosis is squamous cell carcinoma (SCC). In
case of SCC, the following diagnostic procedures are per-
formed: physical head and neck examination at the out-
patient clinic, CT or MRI of the head and neck area, X-ray
or CT of the chest, and endoscopy under general anaes-
thesia of the whole upper aerodigestive tract (panendos-
copy). During the panendoscopy, directed biopsies are
taken from the nasopharynx, the base of the tongue and the
tonsils (or tonsillectomy). Unfortunately, the yield of these
directed biopsies taken during panendoscopy is low. Con-
sequently, a substantial number of UPTs remains unde-
tected with the conventional diagnostic procedures. In case
of UPT, treatment mostly consists of a (modified) radical
neck dissection in combination with irradiation of the
whole pharyngeal axis. The irradiation of this large surface
area aims the elimination of a probably very small (at least
undetectable) malignant primary tumour. Unfortunately,
this radiation treatment may cause considerable iatrogenic
morbidity, e.g. mucositis, xerostomia, mucosal atrophy and
even osteoradionecrosis.
All the diagnostic procedures mentioned are performed
because the detection of the primary tumour is important.
Detection of the primary tumour generally allows for a less
extensive treatment (e.g. smaller radiation field). It may
lead to a more specific therapy which in its turn will give a
more appropriate treatment, resulting in an improved loco-
regional control and lower morbidity.
Several studies have examined the value of 18FDG-PET
for detecting UPT. In a comprehensive review of Rusthoven
et al. [1] on the use of 18FDG-PET for the detection of
UPT which comprises 16 studies with 302 patients, a
sensitivity of 88.3%, specificity of 74.9% and accuracy of
78.8% are observed. Similar results were demonstrated in
more recent studies (PET and PET/CT) and the study
published in this issue [2, 3]. A problem with interpretation
and comparison of these studies is their lack of uniformity
in the inclusion criteria: after physical examination only or
after diagnostic imaging by CT and/or MRI and/or endo-
scopic examination under general anaesthesia with taking
of directed biopsies of areas most likely to harbour an
occult primary tumour. Thus, the definition of UPT differs
among studies. It may be obvious that the chance of
detecting the occult primary tumour is higher in patients in
whom the primary tumour is not found after physical
examination only than in patients who underwent an
extensive diagnostic work-up, including diagnostic imag-
ing. To investigate the additional value of FDG-PET, only
patients with UPT after complete conventional work-up
should be included as in the study published in the present
issue of European Archives of Otorhinolaryngology and
Head & Neck [3].
Moreover, the definition of sensitivity differs between
studies. Most studies used the combined detection results
of all diagnostic techniques during follow-up as reference
standard. In principle, a primary tumour should be present
R. de Bree (&)
Department of Otolaryngology/Head and Neck Surgery,
VU University Medical Center, De Boelelaan 1117,
1081 HV Amsterdam, PO Box 7057,
1007 MB Amsterdam, The Netherlands
e-mail: r.bree@vumc.nl
123
Eur Arch Otorhinolaryngol (2010) 267:1653–1655
DOI 10.1007/s00405-010-1372-2
in all patients (except if spontaneous complete regression is
believed), but that in some patients these tumours will not
be detected or become manifest due to wide field irradia-
tion. Therefore, all undetected primary tumours in those
patients should be considered as false negative. Conse-
quently, the real sensitivity is much lower than the reported
sensitivity (70–100%) [1–4]. The detection rate of occult
primary tumours is probably a more realistic outcome
parameter than sensitivity. Rusthoven et al. [1] found a
detection rate by FDG-PET in 24.5% of patients.
Another aspect is that specificity remains too low
because of too many false-positive results. The tonsils and
the base of tongue appeared to be the localizations with the
highest rate of false-positive findings [1]. This is probably
caused by some asymmetric physiological uptake. It may
be difficult to differentiate between physiological and
pathological uptake in the head and neck area. It is
important to know the specific sites with physiological
uptake in detail when reading FDG-PET scans of the head
and neck [5].
Miller et al. [8] showed in a prospective study (n = 31)
that the combination of 18FDG-PET and a panendoscopy
with biopsies detected 45.2% (14/31) of UPT. Of these 14
cases, 5 patients had a negative PET, but a positive finding
by panendoscopy and biopsies. Therefore, a negative PET
does not preclude the need for panendoscopy with biopsy
to detect the UPT. In addition, they concluded that the
overall risk of subsequent manifestation of a primary
tumour of the upper aerodigestive tract was very low
(5.8%) in patients that have had a negative PET and a
negative panendoscopy with biopsy, demonstrating the
efficacy of this combined approach [6].
In order to decrease false-positive and false-negative
findings, FDG-PET uptake was quantified using standard-
ized uptake value (SUV, i.e. the ratio of measured uptake
in a static scan obtained 60 min after FDG injection over
the injected dose and normalized for volume of distribu-
tion, e.g. bodyweight). PET quantification with SUVs is
affected by many technical and physiological factors. As a
result, differences in FDG-PET study methods hamper the
determination of universal guidelines for interpretation of
FDG uptake. These differences concern patient factors (e.g.
plasma glucose levels), time interval between injection and
scanning, image reconstruction technique, image quality
and SUV measure used. To improve the usefulness of
SUVs, calibration of PET scanners and standardization of
PET-scanning protocols should be performed. Guidelines
for standardization and quantification of FDG uptake have
been developed [7]. Moreover, normal SUV values of FDG
uptake at sites with physiological FDG uptake should be
available to improve distinguishing physiological from
pathological FDG uptake at specific sites.
An important methodological problem is how to deter-
mine the specific contribution of each diagnostic technique.
If, for example, an occult primary tumour in the tonsil is
detected by FDG-PET, it can be anticipated that this pri-
mary tonsillar carcinoma would also have been detected by
tonsillectomy which is part of the conventional (non-FDG-
PET based) work-up. In such a scenario, the additional
value of FDG-PET is questionable.
The most accurate study design to examine the real
additional value of FDG-PET has been used in a pro-
spective, multicentre study in patients with a UPT in which
physical examination, indirect laryngoscopy and CT/MRI
had not revealed the occult primary. All patients underwent
a blinded FDG-PET and a panendoscopy with directed
biopsies. After the panendoscopy, but in the same narcosis
session, the result of the FDG-PET was communicated to
the surgeon, and additional biopsies could be taken based
on these findings. In this Dutch ZonMw-funded multicentre
PRIMUS study, the additional value of FDG-PET was
examined by comparing the conventional standard work-up
with a FDG-PET-based work-up. In this way, the real
additional value of PET-guided biopsies can be deter-
mined. Unfortunately, no results have been published yet.
If FDG-PET is considered to be of real additional value
in detecting occult primary tumours in patients with cer-
vical lymph node metastases of an unknown primary
tumour, the question arises when to perform a FDG-PET
scan. Frequently, patients presenting with cervical lymph
node metastases as first manifestation of cancer have
extensive disease of the neck and are at risk for distant
metastases [8]. Besides, primary tumours outside the head
and neck area can metastasize to the neck. In case of distant
metastases or primary tumours below the clavicles, imag-
ing of the head and neck area and panendoscopy can be
avoided. Another reason to perform FDG-PET upfront may
be waiting time for FDG-PET or other logistic problems.
On the other hand, if the occult primary tumour is detected
by conventional imaging techniques, FDG-PET is not
needed. PET is not without drawbacks, not at least its
availability, costs, radiation exposure, detection of inci-
dentalomas and burden to the patient.
Detection of only about 25% of unknown primary
tumours by FDG-PET does not seem very impressive, but
for the individual patient this means a less extensive
treatment possibly leading to a substantial reduction of
morbidity. FDG-PET should be performed in HNSCC
patients presenting with UPT. However, the real additional
value of FDG-PET has still to be defined. Therefore, a
large multicentre study using aforementioned study design
in a homogeneous (squamous cell carcinoma only) group
of patients with UPT after physical examination and CT or
MRI should be performed.
1654 Eur Arch Otorhinolaryngol (2010) 267:1653–1655
123
Open Access This article is distributed under the terms of the
Creative Commons Attribution Noncommercial License which per-
mits any noncommercial use, distribution, and reproduction in any
medium, provided the original author(s) and source are credited.
References
1. Rusthoven KE, Koshy M, Paulino AC (2004) The role of
fuorodeoxyglucose positron emission tomography in cervical
lymph nodes metastases from unknown primary tumor. Cancer
101:2642–2649
2. Padovani D, Aimoni C, Zucchetta P, Paluzzi A, Pastore A (2009)
18-FDG PET in the diagnosis of laterocervical metastases from
occult carcinoma. Eur Arch Otorhinolaryngol 266:267–271
3. Yabuki K, Tsukuda M, Horiuchi C, Taguchi T, Nishimura G (2010)
Role of 18F-FDG PET in detecting primary site in the patient
with primary unknown carcinoma. Eur Arch Otorhinolaryngol. doi:
10.1007/s00405-010-1371-3
4. Regelink G, Brouwer J, De Bree R et al (2002) Detection of
unknown primary tumours and distant metastases in patients with
cervical metastases: value of FDG-PET versus conventional
modalities. Eur J Nucl Med 29:1024–1030
5. Burrel SC, Van den Abbeele AD (2005) 2-Deoxy-2-[F-18]fluoro-
D-glucose-positron emission tomography of the head and neck: an
atlas of normal uptake and variants. Mol Imaging Biol 7:244–256
6. Miller FR, Karnad AB, Eng T, Hussey DH, Stan McGuff H, Otto
RA (2008) Management of the unknown primary carcinoma: long-
term follow-up on a negative PET scan and negative panendos-
copy. Head Neck 30:28–34
7. Boellaard R (2009) Standards for PET image acquisition and
quantitative data analysis. J Nucl Med 50:11s–20s
8. Senft A, de Bree R, Hoekstra OS et al (2008) Screening for distant
metastases in head and neck cancer patients by chest CT or whole
body FDG-PET: a prospective multicenter trial study. Radiother
Oncol 87:221–229
Eur Arch Otorhinolaryngol (2010) 267:1653–1655 1655
123


Remco de Bree

Bree, R. de

DSpace at VU

2-Deoxy-2-[F-18]ﬂuoroD-glucose-positron emission tomography of the head and neck: an atlas of normal uptake and variants.

Detection of unknown primary tumours and distant metastases in patients with cervical metastases: value of FDG-PET versus conventional modalities.

Hoekstra OS et al (2008) Screening for distant metastases in head and neck cancer patients by chest CT or whole body FDG-PET: a prospective multicenter trial study.

Management of the unknown primary carcinoma: longterm follow-up on a negative PET scan and negative panendoscopy.

Pastore A

Role of 18F-FDG PET in detecting primary site in the patient with primary unknown carcinoma. Eur Arch Otorhinolaryngol.

Standards for PET image acquisition and quantitative data analysis.

The role of fuorodeoxyglucose positron emission tomography in cervical lymph nodes metastases from unknown primary tumor.

http://dare.ubvu.vu.nl/bitstream/handle/1871/34611/256507.pdf?sequence=1&isAllowed=y

The real additional value of FDG-PET in detecting the occult primary tumour in patients with cervical lymph node metastases of unknown primary tumour

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