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Page 2 of 11 Cox et al. J Cancer Metastasis Treat 2021;7:25 https://dx.doi.org/10.20517/2394-4722.2021.55

INTRODUCTION
In a majority of patients with head and neck squamous cell carcinoma (HNSCC), treatment consists of
[1-3]
radiotherapy, and if possible, combined with chemotherapy for locally advanced disease . Current dose
prescription in curative (chemo)radiotherapy [(C)RT] for HNSCC consists of two dose levels. A high “boost
dose”, of around 70 Gy in fractions of 2 Gy (or biologically equivalent: EQD2), is delivered to tumor that
can be detected during diagnostic work-up (i.e., macroscopic disease). A lower “elective dose” of 45-50 Gy
(EQD2) is delivered to the so called elective clinical target volume (CTV elective-nodal ). This often encompasses
large anatomical volumes of the neck containing the lymphatic drainage system and lymph nodes, that are
presumed to harbour tumor deposits that are too small to be detected by diagnostic imaging (i.e.,
“microscopic”, “subclinical”, or “occult” disease). This concept originates from the 1950s and, remarkably,
has not changed to date . At that time, assessment of macroscopic tumor extension was limited to physical
[4]
examination. Therefore, defining the primary tumor was much less accurate, and small lymph node
metastases (short-axis diameter < 10-15 mm) often remained undetected.

In the past few decades diagnostic imaging techniques have evolved rapidly, contributing to a better nodal
staging of the neck in HNSCC. The criterion for pathologic lymph nodes on computed tomography (CT)
was limited to a nodal short-axis diameter ≥ 10 mm, because of a rapidly decreasing specificity for smaller
[5]
nodes . With the use of magnetic resonance imaging (MRI), the detection threshold could be reduced to 7-
10 mm, when assessing morphological features such as border irregularity and inhomogeneity .
[6]
Ultrasound-guided fine needle aspirated cytology (US-FNAC) further improved the detection of smaller
lymph node metastases, mainly based on the excellent specificity of pathological examination, but with
limited sensitivity and inherent inter-operator variability and practical limitations in the number of
[7,8]
evaluable nodes .

Finally, the introduction of positron emission tomography with fluor-18-fluorodeoxyglucose (FDG-PET)
imaging enabled quantitative functional evaluation of lymph nodes in addition to morphologic evaluation.
Since the beginning of this century, the use of FDG-PET/CT in clinical practice for patients with HNSCC
has expanded rapidly, being far more than only a diagnostic tool for disease staging. This review discusses
the role of FDG-PET/CT in radiotherapy of the neck in HNSCC, with implications for diagnostic staging,
dose prescription, adaptive radiotherapy, and post-therapy evaluation.

FDG-PET/CT FOR DIAGNOSTIC EVALUATION, CURRENT PRACTICE
Pre-treatment nodal staging
FDG-PET has the unique ability to perform a quantitative functional evaluation of tissues, as FDG-uptake
[9]
reflects the metabolic activity of tumor cells and can be considered as a surrogate for tumor burden .
Especially in HNSCC, FDG-PET/CT is commonly used for diagnostic evaluation of lymph nodes. Several
large meta-analyses demonstrate a superior accuracy of FDG-PET/CT for lymph node assessment, in
comparison with stand-alone conventional anatomic imaging [10-13] . There are few studies reporting on the
detection threshold of FDG-PET for nodal metastases in HNSCC using histopathological validation.
[14]
Roh et al. examined 4378 lymph nodes in 93 HNSCC patients, finding a mean size of true-positive nodes
of 12.4 ± 6.7 mm vs. 5.7 ± 4.5 mm for false-negative nodes. Similar results were reported in another study,
[15]
suggesting a FDG-PET detection threshold of 5-10 mm . Functional and anatomical imaging modalities
are considered complementary to a certain extent and, when used together, can lower the diagnostic
threshold of nodal tumor deposits to about 5 mm .
[16]