Introduction
Head and neck cancer (HNC) constitutes 5.1%
(>633.000) of all new cancers and relates to 4.8% of all
cancer deaths annually worldwide with Head and Neck
Squamous Cell Carcinomas (HNSCC) contributing by
far the largest number.[] Major risk factors are smoking,
alcohol abuse and HPV infection.[] The main sites
for HNSCC are the larynx, pharynx and oral cavity.[]
The malignancies occurring in this region are generally
diagnosed by clinical, endoscopic examinations and histologic methods, after imaging methods are
used to evaluate the spread and staging of the tumors.
Positron Emission Tomography (PET) and Computed
Tomography (CT) are used together (PET/CT) as a
molecular imaging method. PET scan provides important
information about the metabolic activity and physiology
of the body, while CT images allow the determination
of anatomical changes in the body. Although the
radiopharmaceuticals generally vary according to the
type of cancer, the most frequently used radiopharmaceutical
for cancer imaging is Fluoride-18 Fluorodeoxy-glucose (FDG). As glucose metabolism is increased in
cancer, FDG uptake also increases compared to ground
activity. Maximum standardized uptake value (SUVmax)
and metabolic tumor volume (MTV) are the most
used PET parameters in clinical practice.
PET/CT offers limited local evaluation due to physiological
FDG involvement in the evaluation of tumors
located in areas close to the lymphoid tissues. Distant
metastasis at the time of diagnosis in head and neck
cancers is found in approximately 15% of patients.
Whole-body imaging is of great importance in this patient
group due to the frequent occurrence of second
and third primary malignancies accompanying head
and neck cancers due to similar carcinogenic factors.
[] PET can be quantified with SUV. It has been shown
that SUVmax is strongly related to advanced stage,
lymph node involvement, local extension and tumor
differentiation.[-] MTV has been reported as additional
diagnostic and prognostic imaging biomarkers
in various human solid tumors.
FDG-PET was associated with several histopathological
parameters as reported previously. One
of these is Ki 67, a widely used proliferation index,
which is of prognostic relevance in various tumor
entities.[] However, Meyer et al. reported that there
was a weak correlation between SUV values derived
from FDG-PET and proliferation index Ki 67 in HNSCC
in a large patient sample.[] p16 positive carcinomas
showed significantly lower SUV values than
p16 negative tumors.[,]
There is no study investigating the relationship
between histopathology and PET/CT SUV max and
MTV values of head and neck cancers in the literature.
The goal of this paper is to investigate whether there
is a correlation between FDG-PET/CT SUVmax value
and MTV and histopathological features of head and
neck cancers.
Methods
A total of 52 patients who were diagnosed with primary
head and neck cancer between 2007 and 2019 at
the Department of Otorhinolaryngology & Head and
Neck Surgery of the the Istanbul Training and Research
Hospital Turkey, were retrospectively assessed. Patients
with a prior history of head and neck cancer, neck surgery
and chemoradiotherapy were excluded. All patients
underwent a conventional preoperative work up,
including endoscopy, ultrasound, contrast enhanced
CT, and magnetic resonance imaging (MRI), in addition
to FDG-PET/CT imaging.
A case file review was performed and information
collected regarding age, sex and primary tumor
site. Fifty two patients were divided into two groups as
squamous cell carcinoma (SCC) and other malignant
tumors according to histopathological diagnosis MTV
and SUVmax values of primary tumor were measured
in PET/CT and both groups were statistically compared.
All patients were staged according to the AJCC
classification (7th edition).
18F-FDG PET/CT Imaging Protocol
Patients with blood glucose levels lower than 140 mg/
dl after at least 6 hours of fasting were admitted for
the procedure. Whole-body PET/CT imaging was obtained
including the area from the vertex to the upper
thigh with the patients in the supine position, 60 min
after a standard 3.7?5.2 MBq/kg 18F-FDG intravenous
injection. İmaging performed by Siemens mCT 20 ultra
HD LSO PET/CT (Siemens, Siemens molecular imaging,
Hoffmann Estates, Illinois, USA).
CT imaging for PET/CT was performed using a
multi-detector scanner with 20 slices, at 80-140 kV, 20-
266 mAs, 0.8 pitch and 512x512 matrix [personalized
settings determined by automatic exposure control
system; automatically defined by the software used by
manufacturer (CareDose 4D) depending on the patient
and region assessed]. CT imaging was performed
in craniocaudal direction with 5 mm of slice thickness
and 0.5 seconds of rotation time. Then, PET imaging
was performed in the same range through craniocaudal
direction at 8 to 9 bed positions, 1.5 minutes for
each PET bed. Ultra HD images were acquired using
Time of flight+True X algorithm at iteration 2 and subset
16 values for reconstruction.
Interpretation of PET/CT Images
Images acquired from all patients were evaluated by
a nuclear medicine physician, at the workstation visually
and semi-quantitatively in axial, coronal and
sagittal planes. PET/CT image evaluation was done
unaware of previous imaging results of subjects. For
visual evaluation, foci of increased 18F-FDG uptake
compared to background and CT findings were evaluated
in conjunction. For semi-quantitative analysis,
SUVmax was measured by placing the "volume-ofinterest"
(VOI) around the 18F-FDG positive primary
tumors and nodal metastatic lesions in visual
evaluation. Focal FDG uptakes with an abnormal soft
tissue mass or a lymph node on CT counterpart was
considered significant for malignancy. SUVmax was calculated according to the following formula: Maximum
activity inside the VOI (MBq/gr) /injected 18FFDG
dosage (MBq/kg body mass). A 3-dimensional
globular VOIs including each primary tumor were
drawn manually. MTV(expressed in cm3) was calculated
automatically from PET data by grouping all
spatially connected voxels within a threshold of 40%
of the SUVmax.
Statistical Analysis
Individual and aggregate data were summarized using
descriptive statistics including mean, SD, medians
(minimum-maximum), frequency distributions, and
percentages. Normality of data distribution was verified
using the Kolmogorov-Smirnov test. To compare
distribution among samples, the non-parametric Mann
Whitney U test was used for two samples. Chi-square
test was used in the analysis of qualitative independent
data. A p-value lower than 0.05 was considered to indicate
statistical significance. Statistical analyses were
performed using SPSS® 22.0. software program.
Results
Fifty two consecutive patient"s notes were reviewed,
who presented to the HNC clinic as stated above. The
mean age was 62 (31-94). As expected, there was a
clear male predominance with 44(84.6%) male and 8
(15.4%) female patients. The median SUVmax value
was 17.88 (3-52) and MTV was 5.40 (0-329) for the
whole patients. 31 of the patients were in squamous cell
carcinoma and 21 were in the other malignant tumor
group (Table 1).
Table 1: Patient demographics and clinical characteristics
Distribution of the SCC patient group are shown in
Table 2 and other malignant tumor group sites and histopathologic
distribution are shown Table 3. While the majority of the SCC group was in the larynx, thyroid
and parotid were the most common primary tumor localization
in the other group.
Table 2: Anatomical regions of SCC
Table 3: Cancer subtypes of non-SCC group
No significant difference was established between
the groups in terms of age, gender and MTV (p=0.948,
p=0.166 and p=0.189 respectively). SUVmax value in
SCC group was significantly higher (p=0.003) than the
other group (Table 4). T staging of all patients can be
seen in Table 5. PET and CT images examples of patients
are seen increased FDG uptake in the left sided
vocal cord SCC and thyroid medullary carcinoma in
the right lobe (Figs. 1, 2).
Table 4: Comparison of SCC and non-SCC groups
Table 5: Tumor classification of patients
Fig 1: Thirty seven years old male patient diagnosed
with larynx ca, intense FDG involvement is observed
in the left vocal cord level, in the widest
area narrowing the airway, measuring 2.4x1.8
cm in size (SUVmax: 27.4) in PET/CT performed
for staging.
Fig 2: Lightly hypodense nodule with SUVmax 2.4 in
the right lobe in FDG-PET/CT. L10 in the T10
vertebra and multiple hypermetabolic LAP in
the neck. Thyroid right lobectomy+right neck
dissection: 1.6 cm Medullary thyroid carcinoma
in the right lobe.
Discussion
To the best of our knowledge, this study is the first
study to investigate the relationship between histopathology of head and neck cancers and SUVmax values
and MTV. The primary goal of this study was to investigate
whether there was a correlation between FDGPET/
CT SUVmax value and histopathological features
of head and neck cancers.
Smoking is one of the main risk factors for HNSCC
and the main source of carbon monoxide (CO).
[,] Increased HbCO in HNC patients who
smoke, results in a decreased oxygen unloading capacity
and a rise of HbCO results in a 25 % reduction
in oxygen available to the tumor.[] Also, cigarette
smoke contains nicotine which decreases wound healing by vasoconstriction thus reducing blood flow
to the wound. Nicotine plays a role in tumor progression
and metastasis by increasing oxidative stress
and activating agents such as proteins and NF-kappa
B.[,] In the light of this information we can clearly
see the effect of smoking-induced hypoxia results
tumor aggression in HNSCC.[] The present study
was revealed that SUV max values in the SCC group
were higher than the non SCC group to support the
above information. Previous studies reported that
more than 50% of solid tumors display heterogenous
hypoxic areas irrespective of their size and histological
characteristics.[-] Morever, larger tumor
volume and increasing hypoxia emerged as putative
prognostic imaging biomarkers in HNSCC.[] However,
we found no significant difference between the
two groups for MTV. Tumors with high FDG uptake
have more active tumor metabolism. Some studies
have reported that deterioration of tumor oxygenation
(tumor hypoxia) is associated with chemoradiotherapy
(CRT) resistance.[,]
In a study investigating the role of FDG uptake in
molecular subgroups of 493 primary breast cancer patients,
it was reported that SUVmax value was highest
in apocrine tumors and lowest in lobular carcinomas
and high SUVmax value was associated with aggressive
histopathological subgroups.[]
Zheng et al.[] reported that 18F-FDG PET/CT
SUVmax values were higher in patients with large tumor
size and advanced stage in addition, primary tumor
SUVmax value was an important marker in determining
the invasion of the surrounding tissue in 104
patients with oral squamous cell cancer.
In the study conducted with 97 advanced stage larynx
and hypopharyngeal SCC patients for organ protection
and survi analysis; it has been reported that the
primary tumor SUVmax value may have a predictive
value for preservation of larynx before CRT in hypopharyngeal
cancers, but it is not predictive for organ
preservation in laryngeal cancers and high SUV max
values decrease the possibility of laryngeal preservation.[]
Pencharz et al.[] reported that SUVmax ratio between
tonsils of 1.6 is highly suspicious for SCC and
could be used to direct the site of biopsy. Some malignant
tonsils had normal FDG uptake. In terms of
tonsilla palatina carcinomas, human papilloma virus
(HPV)-positive primary tumors have been found to
demonstrate lower FDG avidity than HPV-negative
tumors.[]
Limitations of the Study
There are several limitations of the present study to address.
First, it is retrospective in nature, therefore the
potential for selection bias exists. Second, the study
analyzed only a small number of patients overall.
Conclusion
In our study, HNSCC have higher SUVmax values than
other malignant tumors. It can be explained by the fact
that The first group has significantly higher rates of
smoking related issues than the non-SCC group, and
the effects of smoking on the hypoxia pathway furthers
the explanation even more.
Acknowledgments: Thank you to Mr Ertan Koç, for the
statistical analysis and comments.
Peer-review: Externally peer-reviewed.
Conflict of Interest: The authors declare that they have no
conflicts of interest related to this study.
Ethics Committee Approval: This is a retrospective study
and written informed consent was obtained from all patients.
Ethics committee approval is not required.
Financial Support: None declared.
Authorship contributions: Concept - S.B., C.G.; Design -
S.B., C.G., A.V.S., E.M. Ö.Y.; Supervision - Ö.Y.; Materials -
S.B., C.G., E.M.; Data collection &/or processing - S.B., C.G.,
A.V.S., E.M.; Analysis and/or interpretation - S.B., C.G.,
E.M.; Literature search - S.B., C.G., A.V.S., E.M.; Writing -
S.B. C.G., A.V.S.; Critical review - None.
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