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Page 10 of 14 Galli et al. J Cancer Metastasis Treat 2022;8:48 https://dx.doi.org/10.20517/2394-4722.2022.19

While therapeutic indications largely rely on pre-therapeutic staging, radiological staging of the neck after
(C)RT is challenging because irradiation induces several morphological changes that render imaging
interpretation more difficult. Microscopically, (C)RT induces the presence of atypical fibroblasts, swollen
endothelial cells, and telangiectasia of thin-walled vessels. These changes manifest macroscopically and
radiologically with the presence of tissue edema, fibrosis, and recurrent or chronic tissue inflammation,
leading to possible erroneous interpretation of LN pathology [30-32] . In a study by our group, Sheppard et al.
demonstrated a significant reduction of LN yield in NDs of previously irradiated patients .
[33]

Detection of neck recurrence after irradiation is radiologically challenging. There is no definite agreement
on the imaging interpretation of pathological LNs in post-irradiated necks. Comparison of studies is
therefore difficult, as most studies do not provide precise descriptions of the radiological criteria used for
diagnosing LN metastases. Our criteria for MRI are in line with the methods described by Mundada et al.
for detection of recurrence after treatment (66% with CRT) in the neck . These authors showed an
[22]
NPV > 90% and LN metastasis prevalence of 14.9%. The prevalence of LN metastasis in our cohort was also
low at 9.7%. Mundada et al. found that the NPV of MRI with diffusion-weighted imaging was very high,
independent of the disease prevalence . The high NPV in our cohort may be explained by the low
[22]
prevalence of the disease itself, as well as the accuracy of the imaging modality. As such, our findings and
those of previous studies need to be interpreted cautiously.

For PET/CT, the criteria for defining a suspicious LN used by our nuclear physicians are SUVmax and
morphological findings. Rosko et al. only reported an FDG uptake above background as a criterion for LN
[18]
metastasis . Therefore, a comparison with our PET/CT scoring criteria is not feasible. Rosko et al. showed
an NPV of 76.7%, which is lower than our own NPV of 96.9% attained with the consideration of several
radiological criteria. Gilbert et al. reported an NPV of 63% with PET/CT-staged neck, but did not report the
radiological criteria used . In all the above-mentioned studies, histopathological confirmation of the
[34]
radiological diagnosis was considered the reference standard.

The reported rates of occult LN metastasis in recurrent HNSCC show considerable variation. In a recent
meta-analysis, Finegersh et al. found an overall rate of occult nodal metastases of 15.4% in primary
[35]
irradiated recurrent HNSCC, and a rate of 27.2% in recurrent supraglottic/transglottic LSCC . This
meta-analysis indicates that patients with hypopharyngeal, supraglottic, or transglottic primaries, locally
advanced disease at the time of recurrence, and with pretreatment LN metastases are at high risk of
presenting with occult neck node disease . A review of the literature by Sanabria et al. found a substantially
[35]
lower rate of occult metastases (ranging from 17.6%-19% in patients undergoing STL for recurrent LSCC)
than in the above-mentioned recurrent supraglottic/transglottic LSCC . A recent systematic review and
[25]
meta-analysis by Lin et al. demonstrated occult nodal disease in 13.7% of radio-recurrent LSCC, without
any statistically significant difference between supraglottic and glottic cancers (17.8% vs. 12%, P = 0.18) . A
[27]
similar rate of 11% occult neck node metastasis was shown in a systematic review and meta-analysis of
[28]
elective ND during STL by Gross et al. .
The difference between the rates reported in the literature and our low prevalence of occult neck node
metastases may be explained by the different imaging modalities used for re-staging. CT-scan was the
predominant modality in the above-mentioned systematic reviews and meta-analyses, whereas only patients
with MRI and/or PET/CT re-staging were included in our study. Given the superior performance of these
two modalities, a lower rate of occult metastases is expected. Consequently, the prominent role of PET/CT
in patients with curative options is widely recognized . Nevertheless, a previous study by Rosko et al.
[36]
showed that PET/CT had an inadequate sensitivity (16.7%) and NPV (76.7%) in neck node re-staging in a