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Galli et al. J Cancer Metastasis Treat 2022;8:48 https://dx.doi.org/10.20517/2394-4722.2022.19 Page 3 of 14

Ethical issues
Approval for this study was obtained from our ethics committee (Cantonal Ethics Committee of Bern). All
patients included in this study were treated at Bern University Hospital (Inselspital), Bern, Switzerland. The
patients’ data were stored anonymously in a database only accessible to the principal investigators of this
study (Galli J, Giger R, Nisa L).

Patients and inclusion criteria
This retrospective study included patients with histopathologically confirmed recurrent LSCC treated
between January 2004 and January 2019. The inclusion criteria were: (1) STL performed with curative intent
after failed (C)RT for LSCC; (2) ND performed along with STL; (3) preoperative staging by MRI and/or
PET/CT; (4) clinical remission for at least 6 months after the end of primary treatment; and (5) follow-up of
at least 12 months in event-free patients.

Extraction of data and evaluation of imaging
The following variables were retrieved and double-checked in a non-blinded manner by two authors
(Galli J, Nisa L): age, initial TNM staging, initial treatment, recurrence TNM staging, details of salvage
surgery performed, results of histopathologic neck node analysis from the salvage surgery, postoperative
adverse events within 30 days scored according to the Clavien-Dindo classification and long-term sequelae,
and status at the time of follow-up . The 7th edition of the UICC classification was used for tumor
[19]
[20]
staging .
MRI and PET/CT sequences were acquired as previously described [21,22] . Briefly, contrast-enhanced MRI
included coronal inversion recovery, axial T1-weighted, axial T2-weighted, and diffusion-weighted
sequences. For PET/CT, a non-contrast-enhanced CT scan from the skull base to midthigh was performed
with the arms elevated, 60 minutes after tracer injection (FDG). This was followed by a dedicated head and
neck acquisition. Then, a contrast-enhanced CT scan was performed. The criteria for classifying LNs as
suspect for metastatic disease on each imaging modality were as follows:

● MRI: LNs with a diameter equal or greater than 10 mm, long/short ratio < 2, presence of necrotic areas,
evidence of extranodal extension, rough borders, ill-defined margins, infiltration of adjacent structures, and
diffusion restriction.

● PET/CT: LNs with a diameter equal to or greater than 10 mm, long/short ratio < 2, perinodal stranding,
rough borders, ill-defined margins, perinodal fat stranding, and high maximum standardized uptake value
(SUVmax). For calculation of SUVmax, circular regions of interest (ROIs) were drawn around LN
metastasis with focally increased uptake on axial slices, and these ROIs were then automatically grown to a
three-dimensional volume of interest according to a 40% isocontour. The SUVmax of the LN metastasis was
calculated according to the formula: standardized uptake value (SUV) = tissue concentration
(Bq/g)/(injected dose [Bq]/body weight [g]). The cut-off value for suspicious LN was two times the blood
pool value.

For the purpose of this study, when suspicious LNs were described on either one or both of the imaging
modalities (MRI and PET/CT), the neck was scored as positive for metastatic involvement. Only when both
modalities were negative were neck LNs considered as being radiologically rcN0. Analysis was performed
on a per-patient basis.