10.14639/0392-100X-N2370
Objective. The presence of cervical lymph node metastases (CLNM) at diagnosis is one of the most relevant negative prognostic factors in patients with head and neck squamous cell carcinoma (HNSCC). The aim of this study was to analyse 2-deoxy-2[18F]fluoro-D-glucose (FDG) PET/CT findings for the identification of primary tumours and CLNM in a sample of patients affected by HNSCC. Moreover, a maximum standardised uptake value (SUVmax) threshold for the detection of CLNM was estimated. Clinical variables (i.e. smoking and alcohol habits), and tumour features (i.e. EBV and HPV positivity) were also evaluated in relation to FDG PET/CT findings.Methods. We retrospectively analysed patients who underwent FDG PET/CT for HNSCC staging between 2015-2020 at the University Hospital of Ferrara. All patients had cytological or histological confirmation of suspected cervical lymph nodes. Results. In total, 65 patients were enrolled (53 males, 12 females, median age 65.7 years). CLNM of patients with smoking habit had significantly higher SUVmax values than those of patients with previous smoking habit and non-smokers (p = 0.04). p16 positive HNSCC demonstrated a trend for higher SUVmax values on CLNM, in comparison to p16 negative tumours (p = 0.089). ROC curve analysis identified 5.8 as the best cut-off value of SUVmax for the detection of CLNM (AUC = 0.62, sensitivity 71.4% and specificity 72.7%). Conclusions. FDG PET/CT is a useful tool to evaluate CLNM in patients with HNSCC, particularly in those with smoking habit and p16 positive disease. A SUVmax cut-off of 5.8, combined with the use of conventional radiological investigations, may represent a useful tool in the identification of CLNM.
text/xml
1827-675X
2370
en
Mirco  Bartolomei
http://creativecommons.org/licenses/by-nc-nd/4.0
ACTA Otorhinolaryngologica Italica
standardized uptake value
Role of 18F-FDG PET/CT in evaluating lymph node status in patients with head and neck squamous cell carcinoma
Text.Serial.Journal
https://www.actaitalica.it/
43
Head and neck
2023-05-23
2022-11-09
2023-07-25
2023-07-25
235-244
1
Mirco  Bartolomei
2023/05/23
10.14639/0392-100X-N2370
235
Nuclear Medicine Unit, Oncological Medical and Specialists Department, University Hospital of Ferrara, Ferrara, Italy
1827-675X
standardized uptake value
en
244
Role of 18F-FDG PET/CT in evaluating lymph node status in patients with head and neck squamous cell carcinoma
https://www.actaitalica.it/article/download/2370/1005
43
ACTA OTORHINOLARYNGOLOGICA ITALICA 2023;43:235-244; doi: 10.14639/0392-100X-N2370




Head and neck


Role of 18F-FDG PET/CT in evaluating lymph node
status in patients with head and neck squamous cell
carcinoma
Ruolo della PET/CT con 18F-FDG nella stadiazione linfonodale dei pazienti
con carcinoma squamocellulare del distretto testa collo
Chiara Bianchini1*, Matteo Caracciolo2,3*, Luca Urso2,3, Andrea Ciorba1, Anna Bonsembiante1, Andrea Migliorelli1,
Virginia Corazzi1, Ilaria Carandina4, Naima Ortolan2,3, Corrado Cittanti2,3, Licia Uccelli2,3, Stefano Pelucchi1,
Stefano Panareo5, Mirco Bartolomei3
1
  ENT and Audiology Department, University Hospital of Ferrara, Ferrara, Italy; 2 Translational Medicine Department, Ferrara
University, Ferrara, Italy; 3 Nuclear Medicine Unit, Oncological Medical and Specialists Department, University Hospital of Ferrara,
Ferrara, Italy; 4 Oncological Medical and Specialists Department, Oncology Unit, University Hospital of Ferrara, Ferrara, Italy;
5
  Nuclear Medicine Unit, Oncology and Haematology Department, University Hospital of Modena, Modena, Italy
* C. Bianchini and M. Caracciolo contributed equally to this work.


SUMMARY
Objective. The presence of cervical lymph node metastases (CLNM) at diagnosis is one of
the most relevant negative prognostic factors in patients with head and neck squamous cell
carcinoma (HNSCC). The aim of this study was to analyse 2-deoxy-2[18F]fluoro-D-glucose
(FDG) PET/CT findings for the identification of primary tumours and CLNM in a sample of
patients affected by HNSCC. Moreover, a maximum standardised uptake value (SUVmax)
threshold for the detection of CLNM was estimated. Clinical variables (i.e. smoking and
alcohol habits), and tumour features (i.e. EBV and HPV positivity) were also evaluated in
relation to FDG PET/CT findings.
Methods. We retrospectively analysed patients who underwent FDG PET/CT for HNSCC
staging between 2015-2020 at the University Hospital of Ferrara. All patients had cytologi-
cal or histological confirmation of suspected cervical lymph nodes.                               Received: November 9, 2022
Results. In total, 65 patients were enrolled (53 males, 12 females, median age 65.7 years).       Accepted: January 21, 2023
CLNM of patients with smoking habit had significantly higher SUVmax values than those
of patients with previous smoking habit and non-smokers (p = 0.04). p16 positive HNSCC            Correspondence
demonstrated a trend for higher SUVmax values on CLNM, in comparison to p16 negative              Andrea Migliorelli
                                                                                                  Department of ENT & Audiology, University
tumours (p = 0.089). ROC curve analysis identified 5.8 as the best cut-off value of SUVmax
                                                                                                  Hospital of Ferrara, via A. Moro 8 (Cona), 44100
for the detection of CLNM (AUC = 0.62, sensitivity 71.4% and specificity 72.7%).                  Ferrara, Italy
Conclusions. FDG PET/CT is a useful tool to evaluate CLNM in patients with HNSCC,                 E-mail: mglndr1@unife.it
particularly in those with smoking habit and p16 positive disease. A SUVmax cut-off of 5.8,
combined with the use of conventional radiological investigations, may represent a useful
tool in the identification of CLNM.                                                                 How to cite this article: Bianchini C, Caracciolo
                                                                                                    M, Urso L, et al. Role of 18F-FDG PET/CT in
KEY WORDS: squamous cell carcinoma,            18
                                                 F-FDG, PET/CT, lymph node metastasis,              evaluating lymph node status in patients with
standardized uptake value                                                                           head and neck squamous cell carcinoma. Acta
                                                                                                    Otorhinolaryngol Ital 2023;43:235-244. https://
                                                                                                    doi.org/10.14639/0392-100X-N2370
RIASSUNTO
Obiettivo. La presenza di metastasi linfonodali laterocervicali (CLNM) al momento della           © Società Italiana di Otorinolaringoiatria
diagnosi è uno dei fattori prognostici negativi più rilevanti nei pazienti affetti da carcinoma   e Chirurgia Cervico-Facciale
squamocellulare del distretto testa-collo (HNSCC). Lo scopo di questo studio è quello di
analizzare i risultati della PET/CT con 2-deossi-2[18F]fluoro-D-glucosio (FDG) nell’iden-                        OPEN ACCESS
tificazione dei tumori primitivi e delle CLNM in un campione di pazienti affetti da HNSCC.        This is an open access article distributed in accordance with
È stata stimata una soglia del massimo valore di captazione standardizzato (SUVmax) per           the CC-BY-NC-ND (Creative Commons Attribution-Non-
l’individuazione di CLNM. I dati ottenuti dalla metodica FDG PET/CT sono stati correlati          Commercial-NoDerivatives 4.0 International) license. The
                                                                                                  article can be used by giving appropriate credit and mentio-
alle variabili cliniche dei pazienti (come l’abitudine tabagica, l’assunzione di alcool) e alle   ning the license, but only for non-commercial purposes and
caratteristiche del tumore (ad esempio, la positività a EBV e HPV).                               only in the original version. For further information: https://
Metodi. Abbiamo analizzato retrospettivamente i dati dei pazienti sottoposti presso l’Azien-      creativecommons.org/licenses/by-nc-nd/4.0/deed.en




                                                                                                                                                          235
C. Bianchini et al.




da Ospedaliera Universitaria di Ferrara, tra il 2015-2020, a FDG PET/CT per la stadiazione di HNSCC. Tutti i pazienti avevano una conferma
citologica o istologica dei linfonodi cervicali sospetti.
Risultati. Sono stati arruolati 65 pazienti (53 maschi, 12 femmine, età mediana 65,7 anni). I pazienti con abitudine tabagica presentavano
valori di SUVmax a livello di CLNM significativamente più elevati rispetto a quelli dei pazienti con pregressa abitudine tabagica e dei non
fumatori (p = 0,04). Gli HNSCC p16 positivi hanno dimostrato una tendenza a un valore di SUVmax più elevato a livello di CLNM, rispetto a
quelli p16 negativi (p = 0,089). L’analisi della curva ROC ha identificato 5,8 come il valore ottimale di cut-off di SUVmax per il rilevamento
delle CLNM (AUC = 0,62, sensibilità 71,4% e specificità 72,7%).
Conclusioni. La FDG PET/CT è uno strumento utile per valutare le CLNM nei pazienti affetti da HNSCC, in particolare se presente abitudine
al fumo e malattia p16 positiva. La metodica PET, abbinata all’utilizzo delle indagini radiologiche convenzionali, ha permesso di ottimizzare
l’iter diagnostico in ambito oncologico del distretto testa-collo, rappresentando anche un utile strumento per l’identificazione delle CLNM.
PAROLE CHIAVE: carcinoma squamocellulare, 18F-FDG, PET/C, metastasi linfonodali latero-cervicali, SUVmax



Introduction                                                             Hospital of Ferrara. All patients with primary HNSCC re-
                                                                         ceiving FDG PET for staging at the Nuclear Medicine Unit
Head and neck cancers are the sixth most frequent neoplasm
                                                                         between January 2015 and December 2020 were identified.
globally and squamous cell carcinoma (SCC) accounts for
                                                                         Patients studied before 2015 were imaged with a different
90% of histological diagnoses 1. In 2021 in the USA, 66,010
                                                                         tomograph and were therefore excluded in order to analyse
new diagnoses of cancer of the oral cavity, oropharynx and
larynx were estimated, with 14,620 deaths from the disease.              uniform records. Only patients with at least one cytologi-
The 5-year survival was estimated to be 66% for oral cavity              cal or histological confirmation of suspected cervical lymph
and pharynx and 61% for laryngeal cancers 2. Worldwide,                  node were enrolled in the study. Patients with previous histo-
the incidence of SCC in the head and neck regions varies                 ry of head and neck malignancies or previous cervical lymph
according to the geographic area and strongly correlates                 nodes treatment (surgical or conservative) were excluded.
with the distribution of risk factors such as alcohol abuse,             An analysis of patients’ records was performed: data on
exposure to tobacco smoke, and viral infections. Smoking                 gender, age, BMI, smoking and drinking habits, clinical
is clearly established as a causal factor in the development             and pathological stage, surgical or conservative treatment,
of SCC at many sites, including the oral cavity, orophar-                tumour grading, p16 status, immunohistochemistry for
ynx, nasopharynx, hypopharynx, and larynx 3. Moreover,                   EBV and HPV, histopathological confirmation of lympho-
the presence of cervical lymph node metastases at the time               vascular invasion, perineural infiltration, and extranodal
of diagnosis is one of the most important prognostic factors             extension (ENE), SUVmax of primary tumour, suspected
and highly influences the patient’s management 4,5. In this              lymph node metastases and suspected distant metastases at
scenario, FDG Positron Emission Tomography/Computed                      staging FDG PET, and identification of suspicious cervical
Tomography (PET/CT) is increasingly being used as staging                lymph node levels according to FDG PET parameters and
tool, for evaluation of treatment response and detection of re-          cytological and histological results were collected.
sidual disease 6,7. In particular, in a meta-analysis carried out        SUVmax of the primary tumour (T) and the two most sus-
by Sun et al., FGD PET showed a sensitivity and specificity              picious lymph node levels (N) were recorded for each pa-
of 84% and 96%, respectively, in identifying regional nodal              tient. Any SUVmax values of both T and N in relation to the
metastases 8. FDG PET can provide an in-vivo representa-                 variables listed above were explored. In order to evaluate the
tion of lesional glucose metabolism, which is correlated with            SUVmax predictivity in identifying cervical nodal metasta-
cell proliferation index and aggressive tumour behaviour 9.              ses, all cases with at least one lymph node suggestive for
Maximum standardised uptake value (SUVmax) is com-                       metastasis at FDG PET corresponding to a metastasis con-
monly used as a semi-quantitative parameter in PET/CT as
                                                                         firmed by cytology or histology in the same neck level were
it expresses the hottest point within a lesion. The aim of this
                                                                         considered positively matching. Therefore, all laterocervical
study was to analyse FDG PET findings in assessment of
                                                                         bilateral levels were evaluated by experienced nuclear physi-
nodal metastases of patients affected by HNSCC, to corre-
                                                                         cians, also analysing the contextual low-dose CT images and
late it with histopathological features and to estimate a maxi-
                                                                         considering SUVmax value of 2.5 as a cut-off.
mum SUVmax threshold for detection of cervical lymph
node metastases by an ROC curve.                                         Smoking was defined as a current daily consumption of
                                                                         cigar or cigarettes. Alcohol consumption was defined as a
                                                                         daily intake of more than 3 units of alcohol (1 unit = 8 g).
Materials and methods                                                    Non-smokers were defined as patients who had stopped
This retrospective study was conducted at the University                 smoking for at least six months.



236
                                                                                                   FDG PET assessment of N-staging in HNSCC




FDG PET acquisition protocol and interpretation                      and 12 females) with a mean age of 65.7 ± 10.6 years (range
All patients were required to fast for 6-8 h and maintain            41-91). The baseline characteristics are shown in Table I.
adequate hydration before the scan. Diabetic patients had            Regarding smoking habit, 33.9% of patients were active
blood glucose measured before 18F‑FDG delivery. Those                smokers, 30.8% were ex-smokers and only 15.4% had nev-
with a fasting glucose above 190 mg/dl were postponed un-            er smoked. The highest prevalence of primary tumours was
til adequate therapy was established. Images were acquired           found in the oral cavity and oropharyngeal (64.6%). In par-
with an acceptable range of 50-70 min after FDG injec-               ticular, 33.9% of patients were affected by oropharynx SCC
tion (1 mCi/10 kg) using a standard technique on a dedi-             (the most affected subsite being the palatine tonsil, 17%), and
cated 3D PET/CT system (Biograph mCT Flow; Siemens                   30.7% by oral SCC (the most involved subsite being the oral
Medical Solutions, Malvern, PA, USA), as suggested by                tongue, 20%). Unknown primaries were present in 13.8% of
the European Association of Nuclear Medicine (EANM)                  cases; other tumour sites in order of frequency were: larynx
procedure guidelines for tumour imaging 10.                          (10.8%), hypopharynx (6.3%), nasopharynx (3.1%) and lip
A low‑dose CT scan (120 kV and 80 mA/s) was performed                (1.5%).
for attenuation correction of the PET emission data acquired         Based on histopathological information about the specimen
from the mid‑thigh to the skull vertex. PET/CT images were           (biopsy or surgical), tumour grading could be established in
processed and analysed on a Syngo.Via Workstation (Siemens           44 cases. Two patients (3.1%) were classified as G1, 23 pa-
Healthineers). Final PET/CT images were reconstructed along          tients (35.4%) as G2, and 19 (29.2%) as G3. In the remain-
axial, coronal and sagittal planes with a dedicated workstation      ing 21 cases, patients lacked anatomopathological analysis
by an expert nuclear medicine physician. A MIP (Maximum              to establish grading since they did not undergo surgery. Most
Intensity Projection) image was stored for each patient. Every       patients (72.3%) had advanced clinical stage (IV).
focal deviation from physiological distribution, background,         Twenty-nine patients underwent first-line surgical treat-
or blood‑pool and liver uptakes was reported, be it hyper- or        ment. In 25 cases, surgical resection margins were free of
hypo‑metabolic. Pathological findings were considered a fo-          disease (R0), whereas in 4 cases, resection margins showed
cal area of increased radiotracer uptake or diffusely increased      microscopic residual disease (R1). Considering also the 9
uptake, excluding sites of physiological distribution, in com-
parison with surrounding tissues. Circular regions of interest
(ROIs) were drawn around the lesion and the system automati-         Table I. Description of the cohort studied.
cally adapted the ROI into 3-dimensional volume of interest           Population features                                    N (%)
(VOI) and SUVmax was then calculated.                                                                                Cohort n = 65 (100%)
                                                                      Gender
Statistical analysis                                                    Male                                               53 (81.5)
A descriptive analysis of all variables with their frequencies          Female                                             12 (18.5)
was performed. Numerical data were expressed as absolute val-         Mean age at diagnosis (years ± SD)                  65.7 ± 10.6
ues, or percentages, or mean ± standard deviation, or median          BMI
(range). For discrete variables, the chi-square (χ2) test was used      Underweight (≤ 18.4)                                6 (9.2)
to investigate a possible correlation between the intra-variable        Normal weight (18.5-24.9)                          31 (47.7)
distribution, pathological lymph node status and FDG PET pos-           Overweight (≥ 25)                                  21 (32.3)
itivity. The correspondence between pathological lymph node             N.A.                                               7 (10.8)
status and FDG PET positivity was also evaluated with a χ2 test.
                                                                      Smoking habit
The mean values of SUVmax on T and N were compared
                                                                        Yes                                                22 (33.8)
to dichotomous variables (t-test) and multimodal variables
                                                                        No                                                 10 (15.4)
(ANOVA). A ROC curve was obtained to estimate the
                                                                        Ex                                                 20 (30.8)
threshold value of SUVmax indicative for lymph node me-
                                                                        N.A.                                                13 (20)
tastasis. All analyses were considered statistically signifi-
cant for p values < 0.05. Statistical analysis was performed          Alcohol consumption
using the SPSS 20.0 program for Windows.                                Yes                                                31 (47.7)
                                                                        No                                                 16 (24.6)
                                                                        Ex                                                  1 (1.5)
Results
                                                                        N.A.                                               17 (26.2)
Patient and tumour characteristics                                                                                            continues     u
A total of 65 patients with HNSCC were included (53 males



                                                                                                                                        237
C. Bianchini et al.




Table I. Description of the cohort studied (follows).                            Table II. Histopathological features in surgically-treated patients.
 Population features                                                  N (%)                                                                      Cohort
 Tumour site                                                                                                                                (n = 38, 100%)
 Oropharynx                                                          22 (33.9)    Surgical margins
    Palatine tonsils                                                  11 (17)       R0                                                       25 (65.8)

    Base of tongue                                                    6 (9.2)       R1                                                        4 (10.5)

    Epiglottic vallecula                                              1 (1.5)       N.A.                                                      9 (23.7)

    Uvula                                                             2 (3.1)     Lympho-vascular invasion
    Soft palate                                                       2 (3.1)       No                                                       31 (81.6)

 Oral cavity                                                         20 (30.7)      Yes                                                       7 (18.4)

    Tongue                                                            13 (20)     Perineural infiltration
    Floor of mouth                                                    2 (3.1)       No                                                       33 (86.8)

    Alveolus and gingiva                                              3 (4.6)       Yes                                                       5 (13.2)

    Buccal mucosa                                                     1 (1.5)     Extranodal extension
    Lip mucosa                                                        1 (1.5)       No                                                       29 (76.3)

 Unknown primary                                                     9 (13.8)       Yes                                                       9 (23.7)
                                                                                 N.A.: not available.
 Larynx                                                              7 (10.7)
    Supraglottis                                                      4 (6.1)
    Glottis                                                           3 (4.6)
                                                                                 were positive, while 18 were negative. In 48 of 65 patients,
 Hypopharynx                                                         4 (6.3)     HPV-DNA research was carried out. Among those, 12 were
    Pyriform sinus                                                    4 (6.3)    positive and 36 resulted negative. Of the 22 patients with
 Nasopharynx                                                         2 (3.1)     SCC localised in the oropharynx, 18 underwent both p16
 Lip                                                                 1 (1.5)     and HPV-DNA testing: in 16 of 18 cases, concordance was
 Grading                                                                         found between the two tests; 9 patients (50%) were posi-
    G1                                                                2 (3.1)    tive for both and 7 patients (38.8%) were negative. Two of
    G2                                                               23 (35.4)   18 patients resulted positive for p16 and negative for HPV-
    G3                                                               19 (29.2)   DNA, respectively. Of the remaining four patients, two
    N.A.                                                             21 (32.3)   underwent only the HPV DNA test resulting in a negative
 Clinical stage
                                                                                 case and a positive case, while two patients underwent only
                                                                                 the test for p16 that resulted negative.
    I                                                                 5 (7.7)
    II                                                               8 (12.3)
                                                                                 Analysis of SUVmax of primary tumour
    III                                                               5 (7.7)
                                                                                 The analysis of SUVmax values of the primary tumour ac-
    IV                                                               47 (72.3)
                                                                                 cording to patients’ variables and tumour characteristics
SD: standard deviation; BMI: Body Mass Index; N.A.: not available.
                                                                                 (Tab. III) revealed a statistically significant correlation with
                                                                                 tumour site and perineural infiltration status (Fig. 1). Naso-
patients diagnosed with cervical SCC metastases from un-                         pharyngeal SCC showed a significantly higher mean SUV-
                                                                                 max value of T compared to other tumour sites (p = 0.01);
known primary, a total of 38 patients underwent surgery
                                                                                 furthermore, mean SUVmax values of T were found to be
as first-line treatment on T or N (Tab. II), while the others
                                                                                 significantly higher in tumours without perineural invasion
were treated with chemo-radiotherapy. Anatomopathologi-
                                                                                 compared to those with documented perineural invasion
cal analysis of the surgical specimen of T or N showed peri-                     (p = 0.048). Nonetheless, these results could be influenced
neural infiltration in 5 cases (13.2%) and lympho-vascular                       by the small number of patients affected by nasopharyngeal
invasion in 7 cases (18.4%). ENE was detected in 9 of 38                         carcinoma with perineural infiltration.
surgical specimens (23.7%).
                                                                                 Analysis of lymph node SUVmax values
Immunohistochemistry correlations                                                The difference in terms of SUVmax values of N between the
In 33 of 65 patients, immunohistochemical investigation                          group of positively vs negatively matching FDG PET find-
of p16 (p16INK4a cyclin-dependent kinase) was carried                            ings and nodal metastases was statistically significant (medi-
out on cytological or histological samples. Fifteen samples                      an SUVmax 16.7 ± 11 vs 6.5 ± 4.8 respectively; p < 0.0001).



238
                                                                                              FDG PET assessment of N-staging in HNSCC




Table III. Analysis of SUVmax of primary tumours.
 Variables                                    N       Mean      SD         T-test   P value     Diff. mean            95% CI
                                                    SUVmax T                                     SUVmax         Lower          Upper
 Gender                                                                    1.289    0.203         4.35          -2.429         11.139
   Male                                      43      19.74     9.82
   Female                                    10      15.38     8.67
 Age
   < 65 years                                24      17.42     12.67
                                                                          -1.024     0.32         -2.73         -8.099         2.629
   ≥ 65 years                                29      20.15      6.23
 BMI
   Underweight                               6       17.70     10.25
   Normal weight                             24      20.24     10.97       0.344    0.710
   Overweight                                17      17.90      8.02
 Alcohol consumption
   Yes                                       16      17.64     7.13
                                                                          -0.475    0.638        -1.485         -7.817         4.846
   No                                        24       1.13     11.04
 Smoking habit
   No                                        8       16.63     8.51
   Yes                                       19      18.50     12.43       1.169    0.845
   Ex                                        17      19.08     6.62
 p16 status
   Negative                                  18      18.12     8.75
                                                                          -0.617    0.543         -1.90         -8.234         4.434
   Positive                                  10      20.05     5.61
 HPV status
   Negative                                  30      17.94     8.81
                                                                          -0.373    0.711         -1.20         -7.768         5.354
   Positive                                   8      19.15     4.21
 Lympho-vascular invasion
   No                                        29      18.90     11.26
                                                                           0.866    0.393         4.543         -6.148         15-235
   Yes                                       5       14.36     7.14
 Perineural infiltration
   No                                        31      19.36     10.53
                                                                           2.053    0.048         12.79          0.102         25.493
   Yes                                       3       6.56      6.04
 Grading
   G1                                        2       20.55     9.40
   G2                                        21      18.49     12.14       0.040    0.961
   G3                                        13      19.51     8.50
 Tumour site
   Oral cavity-Lip                           19      17.96     8.64
   Hypopharynx                                5      19.44     8.72
   Oropharynx                                19      18.06     7.70        3.750    0.010*
   Nasopharynx                                2      42.60     23.19
   Larynx                                     7      18.04     7.93
SD: standard deviation; Diff.: difference.



Patients with higher SUVmax values in cervical lymph                  cording to patients’ variables and tumour characteristics
nodes showed a significantly higher risk of nodal metastasis          (Tab. V) revealed a significant correlation with smoking
confirmed by cytology or histology (Tab. IV, Fig. 2).                 habit: smokers had significantly higher SUVmax values
The analysis of cervical lymph nodes SUVmax values ac-                of N than patients with previous smoking habit and non-



                                                                                                                                   239
C. Bianchini et al.




Figure 1. Pre-surgical FDG. PET/CT scan (A-B): transaxial images of PET/CT and CT (C): maximum intensity projection; (D-E): sagittal images of PET/CT and
CT) of a 71-year-old man with diagnosis of infiltrating squamous cell carcinoma of the larynx metastasised to several left laterocervical lymph nodes. FDG PET/
CT showed intense uptake both at the primary laryngeal lesion and left laterocervical lymph nodes. Afterwards, the patient was treated with surgery followed by
adjuvant chemoradiotherapy.


smokers (median SUVmax values 15.5 ± 10.2, 11.1 ± 8.1                             value of SUVmax of 5.8, with a sensitivity of 71.4% and a
and 7.4 ± 4.1, respectively; p = 0.04).                                           specificity of 72.7% (Fig. 3).
As for SUVmax of T, p16 status did not significantly in-
fluence SUVmax values of N, not even in the group with                            Discussion
oropharyngeal SCC. Nonetheless, all p16 positive patients
showed a trend for higher SUVmax values of N in compari-                          FDG PET is an effective and accurate tool in oncology, which
son to p16 negative ones (median SUVmax 17.1 ± 14.9 vs                            is complementary to conventional radiological methods and is
10 ± 7.4, respectively; p = 0.089).                                               useful for both staging disease and post-treatment evaluation.
The ROC curve to estimate the threshold value of SUV-                             For the head and neck regions, FDG PET is also widely used
max indicative for lymph node metastasis revealed an area                         for an accurate assessment of cervical lymph node status 11.
under the curve of 0.62. This analysis identified a cut-off                       Actually, the presence of cervical lymph node metastases at


Table IV. Matching of FDG PET and cyto/histologic results.
 Variable              FDG PET and cyto/             N               Mean               SD       T-test         P         Diff.               95% CI
                      histologic matching                          SUVmax N                                              mean
                                                                                                                        SUVmax        Lower         Upper
 SUVmax N
                                       No             23               6.51            4.82      -4.218
                                                                                                            < 0.0001     -10.18      -14.991           -5.355
                                       Yes            42              16.69            10.98
SD: standard deviation; Diff.: difference.




240
                                                                                                               FDG PET assessment of N-staging in HNSCC




Figure 2. Staging FDG PET/CT scan. (A): maximum intensity projection; (B-C): transaxial images of PET/CT and CT) of a 61-year-old man affected by a volumi-
nous squamous cell carcinoma involving left base of tongue and epiglottis. Images show intense uptake in correspondence of the primary tumour and particularly
of lymph node metastases. The patient was subsequently treated with surgery followed by adjuvant chemoradiotherapy.


diagnosis is one of the most important negative prognostic
factors in patients with HNSCC, and therefore correct lymph
node staging is necessary for adequate planning of treatment
protocols 12,13. FDG PET is used to predict tumour aggressive-
ness and surgical outcome, and metabolic parameters such as
SUVmax are commonly used for this purpose 14.
In the present study, we aimed to evaluate possible correla-
tions between SUVmax values of both the primary tumour site
and neck lymph nodes and clinical-pathological features of a
cohort of HNSCC patients. Statistical analyses revealed that
nasopharyngeal SCC showed significantly higher mean SUV-
max of T than other primary tumour sites. Lee et al. performed
a retrospective study on 225 patients, comparing FDG uptake
values in benign nasopharyngeal disease versus malignant
nasopharyngeal pathology. The group with nasopharyngeal
carcinoma showed more intense uptake values than the group
with benign pathology (SUVmax 10.4 ± 4.6 vs 3.9 ± 1.4 re-
spectively, p < 0.001). The cut-off of SUVmax indicating
nasopharyngeal malignancies was 6.00 15. Nonetheless, the
study conducted by Ma et al. concluded that FDG uptake in
the nasopharynx could be considered physiological if SUV-                        Figure 3. ROC curve of SUVmax of cervical lymph nodes.



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Table V. Analysis of cervical lymph node SUVmax values according to patient variables and tumour characteristics.
 Variables                           N               Mean                SD          T-test       P value           Diff. mean        95% CI
                                                  SUVmax N                                                           SUVmax      Lower     Upper
 Gender
   Male                                      53        12.92             8.94
                                                                                    -0.270          0.788             -0.91      -7.634    5.818
   Female                                    12        13.83             16.03
 Age
   < 65 years                                31        13.93             13.37
                                                                                     0.600          0.55              1.61       -3.79         7.01
   ≥ 65 years                                34        12.32              6.93
 BMI
   Underweight                                6        11.75             10.33
   Normal weight                             31        13.71             11.56       1.147          0.325
   Overweight                                21         9.47              6.55
 Alcohol consumption
   Yes                                       16         9.73             7.09
                                                                                    -1.012          0.317             -2.47      -7.391    2.448
   No                                        31        12.20             8.32
 Smoking habit
   No                                        10         7.42              4.14
   Yes                                       22        15.51             10.17       3.390         0.042*
   Ex                                        20        11.11              8.06
 EBV status
   Negative                                  5         15.70             9.55
                                                                                      4.96          0.061             11.3       -0.75     23.35
   Positive                                  2          4.40             2.68
 p16 status
   Negative                                  18        10.03             7.43
                                                                                     -1757          0.089             -7.03      -15.19        1.13
   Positive                                  15        17.06             14.93
 HPV status
   Negative                                  36        14.01             9.72
                                                                                    -0.822          0.415             -3.11      -10.72        4.50
   Positive                                  12        17.11             15.41
 Lymphovascular invasion
   No                                        37        11.57             8.49
                                                                                     0.736          0.470             1.50       -2.73         5.73
   Yes                                        8        10.07             4.21
 Perineural infiltration
   No                                        40        11.11             7.38
                                                                                    -0.317          0.766             -1.76      -16.75        2.21
   Yes                                        5        12.88             12.20
SD: standard deviation; Diff.: difference.




max was lower than 7.6, whereas further investigation should                     In the present study, no statistically significant relationship
be required when SUVmax was higher than 11.0 16. A meta-                         was found between SUVmax of both T and N and p16 or
analysis by Li et al. indicated a SUVmax between 7.8 and 18.0                    HPV DNA status. Nevertheless, a trend of lymph node SUV-
as a cut-off threshold in nasopharyngeal carcinoma 17. In the                    max was highlighted, as it tended to be higher in p16-positive
present study, the mean SUVmax of nasopharyngeal SCC was                         than in p16-negative SCC. Tahari et al. conducted a retrospec-
42.6 ± 23.2, and significantly higher than the values currently                  tive study of 123 patients with oropharyngeal SCC who were
available in the literature. However, the sample of patients di-                 screened for high-risk HPV by in situ hybridisation. The mean
agnosed with nasopharyngeal SCC is extremely small com-                          SUVmax of T in HPV-negative SCC was significantly higher
pared to other primary tumour sites, and this inhomogeneity                      than in HPV-positive ones (10.4 vs 12.4, p = 0.007). On the
could be responsible for the SUVmax discrepancies.                               other hand, comparison of medium SUVmax values of cer-



242
                                                                                           FDG PET assessment of N-staging in HNSCC




vical lymph nodes showed that values tended to be higher in        (6.03 ± 4.22 vs 1.98 ± 0.84). Lymph nodes with a SUV-
HPV-positive nodal metastases compared to HPV-negative             max > 5.25 were all found to be involved by metastasis,
ones, even if not statistically significant 18. Kendi et al. in-   with a mean SUVmax of 11.41 ± 3.93 for metastatic lymph
vestigated the association between SUVmax values and p16           nodes with extracapsular extension (ECE) and 5.13 ± 3.60
positivity in a cohort of patients with oral cavity and oropha-    for metastatic lymph nodes without ECE 24. The cut-off val-
ryngeal SCC. Higher medium SUVmax values were shown                ue identified in our study is slightly higher than the values
for p16-positive cervical nodal metastases than those obtained     reported in the literature; the heterogeneity of primary tu-
for p16-negative lesions 19. Often HPV-positive oropharyn-         mour sites could be co-responsible for this result. To date,
geal cancers are diagnosed at more advanced stages and in the      in the literature, there is still no universally accepted SUV-
presence of nodal metastases, which could justify the trend        max threshold for detection of cervical lymph node metas-
identified. Clark et al. defined a cut-off for SUVmax > 10.8       tases. However, in order to standardise SUVmax threshold
that could predict p16 status with an odds ratio of 4.9 20.        values as much as possible, it may be useful to supplement
Another significant finding of the present study (and – to         cervical lymph node SUVmax with other parameters.
the best of our knowledge – the first reported in the litera-      These include lymph node size and background SUVmax.
ture) focused on smoking habit because smokers showed a            Moreover, we would like to highlight that in our study the
significant higher cervical lymph node SUVmax compared             difference, in terms of SUVmax values of cervical nodes
to non-smokers or ex-smokers, even if no difference was            among positively versus negatively matching FDG PET
found considering SUVmax of the primary tumour. Simi-              findings and lymph node metastases, was significant. Con-
larly, in a retrospective study by Pleitz et al. no significant    sidering this point, Lowe et al., in their prospective and mul-
difference was found when comparing the mean SUVmax                ticentre trial, highlighted the high negative predictive value
of T in active smokers versus non-smokers in either the            (≥ 87%) of FDG PET for clinically N0 on the basis of the
group of patients with oropharyngeal cancer or in the group        neck dissection results in a large cohort of 287 patients 25.
with laryngeal cancer. However, to the best of our knowl-          These findings suggest that, nowadays, FDG PET may assist
edge, no data were provided that compared the SUVmax of            the clinician in deciding on the best therapy in HNSCC, inte-
N in smokers to non-smokers 21.                                    grating conventional radiological investigations.
In the present study, the efficacy of PET in detecting cervical    Although the role of FDG PET in the diagnostic approach
lymph node metastases was evaluated: the higher the SUV-           of HNSCC is well known, the available data on its reliability
max, the more likely there was correspondence with a nodal         in distinguishing cervical lymph node SCC metastases from
metastasis confirmed by cytology or histology. ROC analysis        granulomatous diseases or benign reactive lymph nodes is not
of SUVmax values for the detection of cervical node metas-         completely clear to date. For this aim, PET/CT should always
tasis from SCC revealed an area under the curve of 0.62. The       be compared with other conventional imaging methods.
analysis identified the cut-off value of SUVmax at 5.8, with a
sensitivity of 71.4% and a specificity of 72.7%. On a sample
                                                                   Conclusions
of 23 patients with HNSCC, Murakami et al. defined a cut-
off value of SUVmax that varied according to lymph node            Over the last 20 years, FGD PET has become a very popular
size: 1.9 for lymph nodes smaller than 10 mm, 2.5 for those        and important diagnostic tool in the diagnostic algorithm of
between 10-15 mm, and 3.0 for nodes larger than 15 mm.             HNSCC, although it is still complementary to conventional
Based on these data, a sensitivity of 79% and a specificity of     radiological investigations.
99% were calculated 22. Furthermore, Lim et al. on a sample        We found a positive correlation between higher SUVmax
of 74 patients with HNSCC defined a cut-off of SUVmax              values and confirmation of lymph node metastases on
≥ 3.16 for the diagnosis of lymph node metastases, with a          cytology or histopathology, especially in patients with a
sensitivity of 74.4% and a specificity of 84.9%. In addition,      smoking habit. The best cut-off of SUVmax value to detect
the authors suggested the use of a ratio between lymph node        cervical lymph node metastases was 5.8.
SUVmax and background SUVmax of the healthy tissue, in             In the future, the identification of a standardised and reli-
order to standardise evaluation criteria across different cen-     able SUVmax threshold for head and neck regions, com-
tres as much as possible 23.                                       bined with PET derived volumetric parameters and better
In 2015, Kitajima et al. found that PET/CT correctly indi-         morphological definition of images, will allow further im-
cated the primary tumours in all enrolled patients (36 pa-         provement of the reliability of FDG PET.
tients with HNSCC), with a mean SUVmax of 15.5 ± 6.6.
The SUVmax of pathological lymph nodes was signifi-                Conflict of interest statement
cantly higher than the SUVmax of benign lymph nodes                The authors declare no conflict of interest.



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C. Bianchini et al.




Funding                                                                             10
                                                                                         Boellaard R, Delgado-Bolton R, Oyen WJ, et al. FDG PET/CT: EANM
                                                                                         procedure guidelines for tumour imaging: version 2.0. Eur J Nucl Med Mol
This research did not receive any specific grant from funding                            Imaging 2015;42:328-354. https://doi.org/10.1007/s00259-014-2961-x
agencies in the public, commercial, or not-for-profit sectors.                      11
                                                                                         Linz C, Brands RC, Herterich T, et al. Accuracy of 18-F fluorodeoxyglucose
                                                                                         positron emission tomographic/computed tomographic imaging in primary
                                                                                         staging of squamous cell carcinoma of the oral cavity. JAMA Netw Open
Author contributions                                                                     2021;4:e217083. https://doi.org/10.1001/jamanetworkopen.2021.7083
MC, CB, LU, AC, SP: work conceptualization and writing;                             12
                                                                                         Peltenburg B, de Keizer B, Dankbaar JW, et al. Prediction of ultrasound guid-
NO, LU, MC, VC, AB, AM: data curation; IC: statistical                                   ed fine needle aspiration cytology results by FDG PET-CT for lymph node
                                                                                         metastases in head and neck squamous cell carcinoma patients. Acta Oncol
analysis; CC, LU, MB, AC, CB, SP: revision and editing.                                  2018;57:1687-1692. https://doi.org/10.1080/0284186X.2018.1529426.
All authors have read and agree with the final version of                           13
                                                                                         Yamaga E, Toriihara A, Nakamura S, et al. Clinical usefulness of 2-deoxy-
the manuscript.                                                                          2-[18F] fluoro-D-glucose-positron emission tomography/computed tomog-
                                                                                         raphy for assessing early oral squamous cell carcinoma (cT1-2N0M0). Jpn J
                                                                                         Clin Oncol 2018;48:633-639. https://doi.org/10.1093/jjco/hyy065
Ethical consideration                                                               14
                                                                                         Werner J, Hüllner MW, Rupp NJ, et al. Predictive value of pretherapeu-
No Ethical Committee approval was required for this study.                               tic maximum standardized uptake value (Suvmax) in laryngeal and hy-
This study was conducted in compliance with the ethi-                                    popharyngeal cancer. Sci Rep 2019;9:8972. https://doi.org/10.1038/
                                                                                         s41598-019-45462-y
cal standards of the institutional and/or national research                         15
                                                                                         Lee N, Yoo IR, Park SY, et al. Significance of incidental nasopharyngeal
committee and with the Helsinki Declaration (2008); the                                  uptake on 18F-FDG PET/CT: patterns of benign/physiologic uptake and
research did not affect patient care in any way, since only                              differentiation from malignancy. Nucl Med Mol Imaging 2015;49:11-18.
                                                                                         https://doi.org/10.1007/s13139-014-0299-8
patient data were retrieved and reviewed.                                           16
                                                                                         Ma C, Zou R, Huo Y, et al. 18F-FDG uptake characteristics in differentiating
Written informed consent was obtained from each partici-                                 benign from malignant nasopharyngeal lesions in children. Biomed Res Int
pant/patient for study participation and data publication.                               2015;2015:354970. https://doi.org/10.1155/2015/354970.
                                                                                    17
                                                                                         Li Q, Zhang J, Cheng W, et al. Prognostic value of maximum standard
                                                                                         uptake value, metabolic tumor volume, and total lesion glycolysis of posi-
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