10.14639/0392-100X-N2055
Background. This study aimed to evaluate the performance of the 2017 8th TNM edition and the latest update in 2020 compared to the 7th in a large cohort of patients affected by oral tongue squamous cell carcinoma (OTSCC), considering all stages. Materials and methods. The cohort involved 300 patients affected by OTSCC treated with surgery. All cases were classified according to the 7th, 8th (2017), and the latest updated TNM edition (October 2020),. Patients were grouped based on the shift in tumour (T) category, lymph nodal (N) category and final pathological stage. Overall survival (OS) and disease-free survival (DFS) were calculated with the Kaplan-Meier method. Univariate and multivariate analyses were carried out. Results. According to the 7th edition, multivariate analysis OS revealed that stage IV patients had an almost 4-fold risk of death compared to stage I (HR = 3.81 95% CI: 2.32-6.25; p &lt; 0.001). Regarding DFS, stage IV patients had a 2-fold greater risk of relapses, or second primary, than patients in stage I (HR = 2.51 95% CI: 1.68-3.74; p &lt; 0.001). According to 2017 8th edition for OS, stage IV patients presented a 5-fold higher risk of death compared to patients in stage I (HR = 5.18 95% CI: 2.96-9.08; p &lt; 0.001) and almost 4-old greater risk of relapses or second primary compared to patients in stage I considering DFS (HR = 3.61 95% CI: 2.28- 5.71; p &lt; 0.001). Regarding the recent edition of 8th TNM (2020), stage IV patients had an almost 5-fold greater risk of death compared to patients in stage I considering OS (HR = 4.84 95% CI: 2.74-8.55; p &lt; 0.001), while for DFS they had 3-fold greater risk of relapse or second primary compared to patients in stage I (HR = 3.13 95% CI: 1.99-4.91; p &lt; 0.001). Conclusions. This study confirmed that the recent update of the 8th edition of the TNM (2020) improves stratification and identification of advanced tumours, reducing the number of T3 compared to the 2017 edition and increasing the number of patients with pT4. This improvement made by the updated edition may reduce the risk of skipping adjuvant therapy.
text/xml
1827-675X
2055
en
Mohssen  Ansarin
http://creativecommons.org/licenses/by-nc-nd/4.0
ACTA Otorhinolaryngologica Italica
stage migration
Oral tongue carcinoma: prognostic changes according to the updated 2020 version of the AJCC/UICC TNM staging system
Text.Serial.Journal
https://www.actaitalica.it/
42
Head and neck
2022-05-16
2022-02-28
2022-05-23
2022-05-23
140-149
1
Mohssen  Ansarin
2022/05/16
10.14639/0392-100X-N2055
140
Division of Otolaryngology and Head and Neck Surgery, IEO, European Institute of Oncology IRCCS, Milan, Italy
1827-675X
stage migration
en
149
Oral tongue carcinoma: prognostic changes according to the updated 2020 version of the AJCC/UICC TNM staging system
https://www.actaitalica.it/article/download/2055/790
42
ACTA OTORHINOLARYNGOLOGICA ITALICA 2022;42:140-149; doi: 10.14639/0392-100X-N2055




Head and neck


Oral tongue carcinoma: prognostic changes
according to the updated 2020 version
of the AJCC/UICC TNM staging system
Il carcinoma della lingua mobile: i cambiamenti della prognosi in base alla versione
2020 del sistema di classificazione AJCC/UICC TNM
Marta Tagliabue1,2, Rita De Berardinis1, Pietro Belloni3,4, Sara Gandini3, Donatella Scaglione5, Fausto Maffini6,
Rosolino Antonino Mirabella7, Stefano Riccio1, Giugliano Gioacchino1, Roberto Bruschini1, Francesco Chu1,
Mohssen Ansarin1
1
  Division of Otolaryngology and Head and Neck Surgery, IEO, European Institute of Oncology IRCCS, Milan, Italy; 2 Department
of Biomedical Sciences, University of Sassari, Sassari, Italy; 3 Department of Experimental Oncology, IEO, European Institute
of Oncology IRCCS, Milan, Italy; 4 Department of Statistical Sciences, University of Padua, Padua, Italy; 5 Division of Data
Management, European Institute of Oncology IRCCS, Milan, Italy; 6 Division of Pathology, IEO, European Institute of Oncology
IRCCS, Milan, Italy; 7 Department of Otorhinolaryngology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy


SUMMARY
Background. This study aimed to evaluate the performance of the 2017 8th TNM edition
and the latest update in 2020 compared to the 7th in a large cohort of patients affected by oral
tongue squamous cell carcinoma (OTSCC), considering all stages.
Materials and methods. The cohort involved 300 patients affected by OTSCC treated with
surgery. All cases were classified according to the 7th, 8th (2017), and the latest updated
TNM edition (October 2020),. Patients were grouped based on the shift in tumour (T) cat-
egory, lymph nodal (N) category and final pathological stage. Overall survival (OS) and
disease-free survival (DFS) were calculated with the Kaplan-Meier method. Univariate and
multivariate analyses were carried out.
Results. According to the 7th edition, multivariate analysis OS revealed that stage IV patients
had an almost 4-fold risk of death compared to stage I (HR = 3.81 95% CI: 2.32-6.25;
                                                                                                     Received and accepted: March 1, 2022
p < 0.001). Regarding DFS, stage IV patients had a 2-fold greater risk of relapses, or second
primary, than patients in stage I (HR = 2.51 95% CI: 1.68-3.74; p < 0.001). According to 2017
                                                                                                     Correspondence
8th edition for OS, stage IV patients presented a 5-fold higher risk of death compared to patients
                                                                                                     Rita De Berardinis
in stage I (HR = 5.18 95% CI: 2.96-9.08; p < 0.001) and almost 4-old greater risk of relapses        Department of Otolaryngology and Head and Neck
or second primary compared to patients in stage I considering DFS (HR = 3.61 95% CI: 2.28-           Surgery, IEO, European Institute of Oncology
5.71; p < 0.001). Regarding the recent edition of 8th TNM (2020), stage IV patients had an           IRCCS, via Ripamonti 435, 20141 Milano, Italy
almost 5-fold greater risk of death compared to patients in stage I considering OS (HR = 4.84        E-mail: rita.deberardinis@ieo.it
95% CI: 2.74-8.55; p < 0.001), while for DFS they had 3-fold greater risk of relapse or second
primary compared to patients in stage I (HR = 3.13 95% CI: 1.99-4.91; p < 0.001).
                                                                                                       How to cite this article: Tagliabue M, De Berar-
Conclusions. This study confirmed that the recent update of the 8th edition of the TNM
                                                                                                       dinis R, Belloni P, et al. Oral tongue carcinoma:
(2020) improves stratification and identification of advanced tumours, reducing the number             prognostic changes according to the updated 2020
of T3 compared to the 2017 edition and increasing the number of patients with pT4. This                version of the AJCC/UICC TNM staging system.
improvement made by the updated edition may reduce the risk of skipping adjuvant therapy.              Acta Otorhinolaryngol Ital 2022;42:140-149. htt-
                                                                                                       ps://doi.org/10.14639/0392-100X-N2055
KEY WORDS: tongue cancer, TNM, depth of invasion (DOI), prognosis, survival, stage
migration
                                                                                                     © Società Italiana di Otorinolaringoiatria
                                                                                                     e Chirurgia Cervico-Facciale
RIASSUNTO
Obiettivo. Questo studio mira alla valutazione dell’efficacia predittiva dell’8ª edizione                           OPEN ACCESS
del TNM (2017) e dell’ultima versione aggiornata nel 2020 rispetto alla 7a applicandole              This is an open access article distributed in accordance with
in un’ampia coorte di pazienti affetti da carcinoma spinocellulare della lingua mobile,              the CC-BY-NC-ND (Creative Commons Attribution-Non-
considerando tutti gli stadi.                                                                        Commercial-NoDerivatives 4.0 International) license. The
                                                                                                     article can be used by giving appropriate credit and mentio-
Metodi. Il gruppo di studio consta di 300 pazienti affetti da carcinoma spinocellulare della         ning the license, but only for non-commercial purposes and
lingua mobile trattati chirurgicamente. Tutti i casi sono stati classificati in base alla 7a, 8a     only in the original version. For further information: https://
(2017) e all’aggiornata (ottobre 2020) edizione del TNM. I pazienti sono stati raggruppati           creativecommons.org/licenses/by-nc-nd/4.0/deed.en




140
                                                                                  Oral cancer: prognostic changes according to the 2020 TNM edition




in base alla migrazione della categoria del tumore (T), dello stato linfonodale (N) e dello stadio patologico finale. La sopravvivenza globale
(OS) e la sopravvivenza libera da malattia (DFS) sono state calcolate con il metodo Kaplan-Meier. Sono state effettuate analisi univariate e
multivariate.
Risultati. Secondo la 7a edizione, l’analisi multivariata della OS mostra che i pazienti in stadio IV hanno un rischio di morte quasi quadruplo
rispetto a quelli in stadio I (HR = 3,81 IC 95%: 2,32-6,25; p < 0,001). Per quanto riguarda la DFS, i pazienti in stadio IV hanno un rischio
due volte maggiore di recidive, rispetto ai pazienti in stadio I (HR = 2,51 IC 95%: 1,68-3,74; p < 0,001). Secondo l’8ª edizione del 2017, per
quanto riguarda l’OS i pazienti in stadio IV hanno un rischio di morte cinque volte superiore rispetto ai pazienti in stadio I (HR = 5,18 IC 95%:
2,96-9,08; p < 0,001) e un rischio quasi quattro volte maggiore di recidiva o secondo tumore rispetto ai pazienti in stadio I considerando la
DFS (HR = 3,61 IC 95%: 2,28-5,71; p < 0,001). Per quanto riguarda la recente edizione dell’8a TNM (2020), i pazienti in stadio IV presentano
un rischio di morte quasi cinque volte maggiore rispetto ai pazienti in stadio I considerando OS (HR = 4,84 IC 95%: 2,74-8,55; p < 0,001),
mentre riguardo alla DFS, presentano un rischio tre volte più elevato di sviluppare recidive o secondi tumori rispetto ai pazienti in stadio I
(HR = 3,13 IC 95%: 1,99-4,91; p < 0,001).
Conclusioni. Questo studio ha confermato che il recente aggiornamento dell’8a edizione del TNM (2020) migliora la stratificazione e
l’identificazione dei tumori in stadio avanzato, in particolare riducendo la numerosità dei T3 rispetto all’edizione 2017 e aumentando quella
dei pT4. In questo modo, si riduce la possibilità di non eseguire la terapia adiuvante a causa della diversa stadiazione del TNM.
PAROLE CHIAVE: carcinoma della lingua, TNM, profondità d’invasione (DOI), prognosi, sopravvivenza, migrazione di stadio




Introduction                                                              mum diameter and deep infiltration helped distinguish T3
                                                                          from T4a tumours 9.
Oral tongue squamous cell carcinoma (OTSCC) is the most
                                                                          Concerning lymph node category, the 8th TNM edition in-
common neoplasia of the oral cavity 1,2, accounting for
                                                                          cluded ENE, defined as the extension of metastatic carcino-
about 25-40% of all oral malignancies 3 with a 5-year over-               ma from within a lymph node through the fibrous capsule
all survival (OS) and disease-free survival (DFS) of about                and into the surrounding connective tissue 10. In detail, the
50% and 60%, respectively 3,4. OTSCC generally stands out                 extranodal extension < 3 cm in diameter in a single node is
by a high rate of lymphatic neck metastasis, a high risk of               staged as pN2a, and all other cases with ENE (ENE+) are
local recurrence and the possibility to develop drug resist-              classified as pN3b 10-12.
ance to chemotherapy during systemic treatment 4,5.                       The purpose of this study, comparing the three versions of
Even if tumour depth of invasion (DOI) – defined as the                   TNM, was to evaluate the performance of recent editions
distance between the level of the basement membrane of                    (2020) of the AJCC Cancer Staging Manual to understand
the closet adjacent normal mucosa and the deepest point                   how it improves oral tongue cancer staging considering the
of tumour invasion 6 – was already associated with an in-                 main prognostic factors (ENE, DOI, tumour diameter) and
creased risk of lymph node metastasis 7, it was not included              how it may better define and stratify prognosis.
in the 7th edition of the staging system for oral squamous
cell carcinoma (SCC) 8.
In 2017, the new 8th TNM edition of the AJCC/UICC stag-                   Materials and methods
ing system introduced DOI in oral tumour classification                   This is a retrospective cohort of 300 consecutive patients
and added extranodal extension (ENE) to the lymph node                    affected by oral tongue squamous cell carcinoma (OTSCC)
category (N) in the pathological and clinical stage as nega-              treated with surgery and adjuvant therapy at the Division
tive prognostic factors. Therefore, primary tumours catego-               of Otorhinolaryngology and Head and Neck Surgery of the
rised as T1 according to the 7th edition were upstaged to T2              European Institute of Oncology, IRCCS (IEO) from January
in the presence of a 5 mm invasion beyond the basement                    2010 to December 2017.
membrane. Primary tumours formerly categorised as T2, or                  Inclusion criteria was newly diagnosed with mobile tongue
even T1, were upstaged to T3 if DOI > 10 mm.                              squamous cell carcinoma treated with surgery followed by
Additionally, on 6th October 2020, the AJCC/UICC stag-                    adjuvant therapy based on histopathological findings and
ing system published an erratum edition of TNM, updat-                    all stages according to AJCC 7th edition.
ing the definition of T4 for oral cavity cancer 9. Despite                We excluded pre-treated patients (prior surgery, radiother-
the previous classification, pT4a oral cavity cancer was                  apy, radio-chemotherapy), other histotypes than SCC, and
defined as a tumour > 4 cm in greatest dimension, and                     the presence of distant metastasis at diagnosis.
> 10 mm DOI or those invading through the cortical bone                   According to the good clinical practice guideline, all useful
of the mandible, maxilla, maxillary sinus or skin of the                  variables and study data were collected and analysed in a
face. The new tridimensional criteria in terms of maxi-                   specifically-designed database.



                                                                                                                                              141
M. Tagliabue et al.




Histopathological features collected: grading (G1-3),             Table I. Clinical and histopathological characteristics of the cohort (n = 300).
maximum tumour diameter (T) (mm), tumour infiltration              Variables                                                        n (%)
(DOI) (mm), multifocality, vascular (LVI) and perineural           Median age (IQR)                                           59 years (70.25-
infiltration (PNI), intrinsic and extrinsic tongue muscle                                                                           46)
involvement, status of surgical margins, total number and          Sex
pathological lymph nodes removed, presence of ENE or                  M                                                            170 (57)
lymph node micro-metastases, T-N tract status (free or                F                                                            130 (43)
involved by disease) 13. Based on the 7th pathological (c)         Smoking
TNM edition, we reported the clinical tumour stage. Each              No                                                           114 (38)
case of OTSCC was re-studied according to the 8th TNM                 Yes                                                          107 (36)
edition 2017 11 and the recent errata version (2020) of the           Ex-former                                                     76 (25)
TNM staging system 9. All cases without data on DOI were              Pack/year                                                       29
reviewed by a head and neck pathologist (FAM) according            Alcohol habits
to the current definition of DOI 14. Patients with involvement        No                                                           198 (66)
of extrinsic tongue musculature by disease were considered            Yes                                                           81 (27)
with a DOI greater at least than 10 mm 15.                            Ex former                                                     11 (4)
We also described postoperative adjuvant therapies (radio-
                                                                      Former                                                         6 (2)
therapy or radio-chemotherapy) performed according to
                                                                      Drinks/day                                                      4
the 7th pathological stage TNM.
                                                                   Tongue tumour site
All patient follow-ups were reported and updated to assess
                                                                      Margin                                                       238 (79)
their status at the last follow-up date.
                                                                      Body/dorsum                                                   27 (9)
We analysed the trend of each stage and T category migra-
tion according to each type of TNM system staging.                    Ventral tongue                                                23 (8)
To evaluate the possible impact of the two last TNM editions          Posterior third                                               12 (4)
on survival rates, we performed OS and DFS analysis compar-        Adjuvant therapy
ing the equal-, up- and down-staged categories. The agreement         RT                                                          87 (29)
between the clinical tumour staging (cTNM) and pathological           CRT                                                         56 (19)
tumour staging (pTNM) 7th edition was also evaluated.              Median follow-up                                              53 months
                                                                   Follow-up status
Statistical analysis                                                  NED                                                         177 (59)
Clinical characteristics were compared using the Pearson              AWD                                                          15 (5)
Chi-square test for categorical variables and Wilcoxon rank           DOD                                                          80 (27)
test for continuous variables. All survival curves were con-          DOC                                                          28 (9)
structed using the Kaplan-Meier method and compared by             Site of recurrence                                             99 (33.0)
log-rank test.                                                        T                                                            13 (13)
Overall survival (OS) was defined as the time from sur-               N                                                            46 (47)
gery to the patient’s death for any cause or the last available       Loco-regional (T+N)                                           7 (7)
follow-up. Disease-free survival (DFS) was defined as the             Loco-regional and distant (T/N + M)                          11 (11)
time from surgery to the progression of the disease, second           Metastasis                                                   22 (22)
primary, death from any cause, or the last available follow-       Second tumour                                                   12 (4)
up. We compared 5-year OS and DFS. The prognostic val-
                                                                      Head and neck cancer                                         7 (58)
ue of the TNM stage in the three editions was evaluated by
                                                                      No head and neck cancer                                      5 (42)
Cox proportional hazard models adjusting for age. For all
                                                                   Grading
tests, the significance level was set at p < 0.05. All analyses
                                                                                             G1                                     62 (20)
were performed using the software R ver. 3.6.0 - “Planting
                                                                      G2                                                           138 (46)
of a Tree” (R Core Team 2019) 16.
                                                                      G3                                                            67 (22)
                                                                      Missing                                                       33 (11)
Results                                                            Micro-metastasis
The study included 300 patients, and demographic-clinical             No                                                           293 (98)
features are summarised in Table I. There were 170 males
                                                                                                                                               u



142
                                                                                              Oral cancer: prognostic changes according to the 2020 TNM edition




Table I. Clinical and histopathological characteristics of the cohort (n = 300)       Migration stage
(follows).
                                                                                      Clinical and pathological TNM according to 7th, 8th (2017),
  Variables                                                       n (%)               and recently updated version (2020) of TNM edition are re-
    Yes                                                              7 (2)            ported by Figure 1. No staging change occurred in 67% of
 Multifocality                                                                        cases (n = 200), while 8% (n = 23) of cases were up-staged
    No                                                             293 (98)           and 22% (n = 65) were down-staged, according to the 2017
    Yes                                                              7 (2)            8th TNM edition staging system.
 Margin status                                                                        Comparing the 7th and the 2020 8th edition, no change in
    Free                                                           268 (89)           staging occurred in 71% of cases (n = 213), while 9%
    Positive                                                        20 (7)            (n = 27) of cases were up-staged and 16% (n = 48) were
    Close (< 1 mm)                                                  12 (4)
 Vascular infiltration
                                                                                      A
    No                                                             282 (94)
    Yes                                                             18 (6)
 Intrinsic muscle infiltration
    No                                                              57 (19)
    Yes                                                            243 (81)
 Extrinsic muscle infiltration
   No                                                              144 (48)
   Yes                                                             156 (52)
 T-N status
   Not removed                                                     139 (46)
   Free from disease                                               117 (39)
   Involved by disease                                              44 (15)           B
 ECE
   No                                                              231 (77)
   Yes                                                              69 (23)
RT: radiotherapy; CRT: chemo-radiotherapy; NED: Non-Evidence of Disease; AWD: Alive
with Disease; DOD: Dead of Disease; DOC: Dead of Other Causes; T: tumour; N: nodal
status; ECE: extracapsular extension; IQR: Interquartile range.




(57%). Median age was 59 years (interquartile range [IQR]:
70.25-46). The lingual margin was the most frequent sub-
site involved by cancer (79%). The histopathological fea-                             C
tures of our sample are summarised in Table I.
Regarding postoperative therapies: overall, 143 patients
(48%) underwent adjuvant therapy; 87 cases underwent ad-
juvant radiotherapy (29%), while 56 patients (19%) needed
radio-chemotherapy. Beyond the stage, the risk factors con-
sidered to perform the adjuvant radiotherapy were extrinsic
muscles involved by the tumour (52%), vascular invasion
(6%), T-N tract involved by cancer (15%) and positive or
close margins (11%). Radio-chemotherapy was reserved
for ECE+ patients (23%) (Tab. I).
The median follow-up was 53 months. At last follow-up,
177 (59%) were alive with no evidence of disease (NED),
and 15 (5%) were alive with disease (AWD). Eighty pa-
tients (27%) died because of tongue cancer disease (DOD),                             Figure 1. Migration of the pathological system staging of T (a), N (b) and
and 28 (9%) died for other causes (DOC) (Tab. I).                                     stage (c) according to 7th, 8th and the updated 8th edition.



                                                                                                                                                          143
M. Tagliabue et al.




down-staged. Considering stages I and II, the change was                   Survival curves
the same for each 8th edition (2017 and 2020). Among 96                    OS at 3 (OS-3yrs) and five years (OS-5yrs) was 70% and
patients staged previously as stage I (7th edition), 4 cases               60%, respectively. DFS at 3 (DFS-3yrs) and five years
became stage III, 13 cases stage II and 79 cases remained                  (DFS-5yrs) was 60% and 50%, respectively (data not
stage I.                                                                   shown).
In addition, of 23 cases previously staged as II (7th edition),
5 cases became stage III and the remaining 18 cases stage                  Survival analysis 7th TNM edition
II.                                                                        Figure 1a shows OS-5yrs related to the 7th TNM edition:
For stages III and IVa, the application of the recently up-                80% for stage 0-I, 75% for stage II, 85% for stage III and
dated version of TNM (2020) showed a different migration                   48% for stage IV (p < 0.01).
compared to the 8th 2017 version.                                          DFS-5yrs was 65% for stage 0-I, 55% for stage II, 60% for
Among 12 cases previously staged as stage III (7th edition),               stage III and 47% for stage IV, (p < 0.01) (Fig. 1b).
1 case became stage IVa according to the 8th TNM 2017                      Multivariate analysis revealed that stage IV patients had
edition, while applying the updated version (2020) 3 cases                 an almost 4-fold risk of death (OS) compared to stage I
became stage IVa.                                                          (HR = 3.81 95% CI: 2.32-6.25; p < 0.001). Stage IV pa-
Moreover, of 147 cases previously staged as IVa (7th edi-                  tients had more than twice the risk of events (DFS) com-
tion), 65 cases became stage III and 47 cases became stage                 pared to patients in stage I (HR = 2.51 95% CI: 1.68-3.74;
IVb based on the 2017 8th TNM edition. Applying the 2020                   p < 0.001) (Tab. II).
TNM on 147 cases previously staged as IVa (7th edition),
48 cases became III, 47 became stage IVb, and 52 patients                  Survival analysis 8th TNM edition, 2017
remained IVa.                                                              For the 8th TNM 2017 edition of the staging system, OS-


Table II. Multivariate analysis using Cox regression.
                                                                    HR     Low 95% CI          Up 95% CI              P-value
 TNM 7th                          DFS        Stage II vs stage I    1.08      0.48               2.44                 0.855
                                             Stage III vs stage I   1.22      0.43               3.45                 0.707
                                             Stage IV vs stage I    2.51      1.68               3.74                < 0.001
                                                    Age             1.02      1.01               1.03                < 0.001
                                   OS        Stage II vs stage I    0.66      0.20               2.23                 0.504
                                             Stage III vs stage I   1.07      0.25               4.58                  0.93
                                             Stage IV vs stage I    3.81      2.32               6.25                < 0.001
                                                    Age             1.03      1.01               1.04                < 0.001
 TNM 8th                          DFS        Stage II vs stage I    1.12      0.56               2.26                 0.742
                                             Stage III vs stage I   1.50      0.91               2.48                 0.110
                                             Stage IV vs stage I    3.61      2.28               5.71                < 0.001
                                                    Age             1.02      1.01               1.03                < 0.001
                                   OS        Stage II vs stage I    0.86      0.34               2.20                 0.761
                                             Stage III vs stage I   2.18      1.19               3.98                 0.011
                                             Stage IV vs stage I    5.18      2.96               9.08                < 0.001
                                                    Age             1.03      1.01               1.04                < 0.001
 TNM 8th (suppl.)                 DFS        Stage II vs stage I    0.97      0.47               2.02                  0.93
                                             Stage III vs stage I   1.26      0.72               2.18                  0.42
                                             Stage IV vs stage I    3.13      1.99               4.91                < 0.001
                                                    Age             1.02      1.01               1.03                 0.001
                                   OS        Stage II vs stage I    0.89      0.34               2.30                 0.805
                                             Stage III vs stage I   1.73      0.88               3.42                  0.11
                                             Stage IV vs stage I    4.84      2.74               8.55                < 0.001
                                                    Age             1.03      1.01               1.04                < 0.001




144
                                                                     Oral cancer: prognostic changes according to the 2020 TNM edition




5yrs was 80% for stage 0-I, 78% for stage II, 65% for stage    pN2a in the 8th (2017 and 2020), and 26 patients remained
III and 40% for stage IV (p < 0.01) (Fig. 1c).                 as pN1.
DFS-5yrs was 70% for stages 0-I, 62% for stage II, 55% for     Among 56 pN2b, 40 cases became pN3b, and 18 remained
stage III and 45% for stage IV (p < 0.01) (Fig. 1d).           pN2b. Nineteen patients were pN2c according to the 7th
Multivariate analysis for OS stage IV patients revealed        edition: 17 became pN3b, 2 remained pN2c, and one pN3
a 5-fold greater risk of death compared to patients in         remained pN3b according to the 8th edition TNM staging
stage I (HR = 5.18 95% CI: 2.96-9.08; p < 0.001), and          system.
almost 4-fold greater risk of events compared to patients
in stage I considering DFS (HR = 3.61 95% CI: 2.28-5.71;       Survival analysis - tumour (T) classification
p < 0.001).                                                    Concerning 5-yr OS, we observed no differences on T1,
                                                               T2, T3 and T4 category according to each type of TNM
Survival analysis 8th TNM edition, 2020                        system staging (respectively: p = 0.83, p = 0.95, p = 0.60,
Concerning the update 8th TNM version (2020), OS-5yrs          p = 0.13) (data not shown).
was 80% for stage 0-I, 78% for stage II, 70% for stage III,    In the same way, no significant differences were found
and 40% for stage IV (p < 0.01) (Fig. 1e).                     for 5-yr DFS on T1, T2, T3 and T4 category according to
DFS-5yrs was 74% for stages 0-I, 72% for stage II, 60% for     each type of TNM system staging (respectively: p = 0.95,
stage III and 32% for stage IV (p < 0.01) (Fig. 1f).           p = 0.87, p = 0.75, p = 0.22) (data not shown).
OS stage IV patients had an almost 5-fold greater risk
of death compared to patients in stage I considering OS        Changing in postoperative treatments according to the new
(HR = 4.84 95% CI: 2.74-8.55; p < 0.001) and, considering      TNM staging
DFS, a 3-fold greater risk of events compared to patients in   Focusing on adjuvant therapy for stage IVa (158 patients,
stage I (HR = 3.13 95% CI: 1.99-4.91; p < 0.001) in multi-     7th edition): 80 patients underwent radiotherapy and 49
variate analysis.                                              underwent radio-chemotherapy. Considering this group
Comparing the 7th with the 2017 TNM edition 5-yr OS and        (158 IVa stage patients, 7th edition), 65 cases were down-
5-yr DFS, we observed that up-staged 5-yr OS was worse,        staged according to the 2017 8th edition, and among those,
while in the case of down-staged patients 5-yr OS was          33% (n = 53) underwent radiotherapy, while one patient
improved (p < 0.001) (Fig. 3).                                 received radio-chemotherapy due to ECE+. Equal-staged
There were no significant differences in OS or DFS com-        occurred in 35 cases, 12 patients (8%) received radio-
paring 7th ed. with the updated TNM (2020) (p = 0.10 and       chemotherapy, and 17 (11%) radiotherapy.
p = 0.06 respectively) (Fig. 2).                               According to the 2020 8th TNM, among 48 down-staged to
Finally, older age in multivariate analysis was confirmed      stage III, one patient received radio-chemotherapy, and 40
as an independent negative prognostic factor for survival      (25%) patients received radiotherapy. Concerning patients
(OS and DFS), considering each TNM staging (p < 0.001)         up-staged according to the 2017 and 2020 8th editions,
(Tab. II).                                                     among 47 restaged as IVb, 10 patients (6%) underwent ra-
                                                               diotherapy, while 36 (23%) patients received radio-chemo-
Changes in tumour (T) and lymph nodal status (N) clas-         therapy. Equal-stage occurred in 52 cases, and 12 patients
sification                                                     (8%) received radio-chemotherapy and 30 (19%) radio-
Focusing on the tumour (T) category, 107 cases defined as      therapy alone.
pT1 (7th edition) were up-staged to pT2 and pT3, respec-       Considered the adjuvant therapy of stage III (12 cases ac-
tively, in 18 and 5 cases, while 84 patients were equal-       cording to 7th TNM edition): five patients underwent post-
staged as pT1, based on both 8th editions of TNM.              operative radiotherapy, of which 1 case was upstaged to
Nine cases of 35 defined as pT2 were up-staged to pT3,         IVa due to ECE+ in the 8th edition (2017 and 2020). The
while 26 patients were equal-staged as pT2, based on both      remaining 12 cases had risk factors for postoperative radio-
two 8th editions of TNM.                                       therapy (T-N tract involved by disease, PNI and LVI).
Among 142 pT4a (7th TNM), 128 and 88 patients were             Concerning the 2020 8th TNM, 3 cases were upstaged to
down-staged to pT3 based on the previous and recent 8th        IVa (stage III in the 7th edition) and underwent postopera-
edition. In addition, 5 and 45 patients were equal-staged      tive radiotherapy.
as pT4a, based on the previous and recent 8th editions, re-
spectively.                                                    Clinical and pathological tumour stage agreement
According to lymph nodal status (N), the “migration” ob-       The comparison between the clinical tumour staging (cT-
served was: 10 patients with pN1 in the 7th edition became     NM) and pathological tumour staging (pTNM) 7th edition



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M. Tagliabue et al.




Figure 2. OS (a) and DFS (b) with the TNM 7th edition; OS (c) and DFS (d) with the previous TNM 8th edition; OS (e) and DFS (f) with the updated TNM 8th edition.


indicated good agreement, with a Cohen’s kappa of 0.71                             agreement of about 36.5%, with a Cohen’s kappa of 0.41
(95% confidence interval [95% CI]: 0.64-0.78) (data not                            (95% CI: 0.21-0.30) (data not shown). The same evaluation
shown). Whereas the comparison of clinical staging cTNM                            with the updated (2020) 8th edition revealed an excellent
with pTNM based on the previous 8th edition indicated a fair                       agreement of 47.4% (95% CI: 0.27-0.39) (data not shown).



146
                                                                                        Oral cancer: prognostic changes according to the 2020 TNM edition




Figure 3. OS (a) and DFS (b) related to the change of stages between the 7th and 2020 8th TNM edition.




Figure 4. OS (a) and DFS (b) related to the change of stages between the 7th and 2017 8th TNM edition.



Discussion                                                                      sified as T3 by the 7th edition was very small (6 patients).
                                                                                As already published 17, the 8th 2017 version led to a sig-
This study on a large monocentric cohort (300 patients af-
                                                                                nificant increase in tumours classified as T3: in our study,
fected by mobile tongue SCC) investigated the performance
                                                                                there were 146 patients according to this edition compared
of the 8th edition of the AJCC Cancer Staging Manual, con-
sidering the last two versions (2017-2020), compared with                       to only 6 in the 7th edition.
the 7th edition in terms of survival outcomes (OS and DFS).                     However, the changes made in the updated edition (2020)
The most evident change concerns pT3 and pT4a: the 2017                         seems to balance these categories by redistributing the
8th TNM application led to a considerable increase of pT3                       number of tumours classified as T3 and T4 and by rebal-
tumours. Conversely, the recent version of the 2020 TNM                         ancing relative prognosis: in our cohort, 104 patients were
led to a more uniform re-distribution of stages pT3 and                         re-classified as T3 and 47 patients as T4a (5 patients were
pT4a compared with the 2017 8th edition.                                        T4a according to the 8th edition 2017).
The main finding of this work is that the tumour group clas-                    Focusing on T survival rates (OS and DFS), we did not ob-



                                                                                                                                                    147
M. Tagliabue et al.




serve any relevant difference for either T1 or T2, according     As is well known, DOI allows better discrimination be-
to the different TNM staging systems 18.                         tween small oral cancers with limited superficial extension
The 5-yr DFS of T3 and T4a, according to the updated 2020        but which are deeply invasive. In contrast, those that are
version, was better than the 8th TNM 2017 edition. Hence,        less invasive have better prognosis, independently of the
the stage III 5-yr OS was worse, according to the 2017           external dimension 19.
8th TNM edition. We did not find any difference between          Concerning postoperative therapies, all the upstaged cases
the two versions of the 8th TNM for stage IV: 5-yr OS was        by the 8th TNM edition could have been spared adjuvant
worse when considering the last two editions than the 7th        therapies according to the 7th edition. Even in our experi-
TNM.                                                             ence, and following the 7th edition, advanced stages (IVa
After analysis of survival rates in terms of DFS for the three   and IVb) underwent adjuvant therapies due to the presence
TNM editions, we can assume that the 8th edition 5-yr DFS        of independent oncological risk factors (PNI, ECE+, LVI,
is better for stage II, while we registered a worsening of       N>1, pT3).
the 5-yr DFS for stage IV in the updated 2020 8th TNM.           Moreover, all cases of tongue cancer involving the posterior
Nevertheless, in the 2017 8th TNM edition staging system,        third of the mobile tongue could have resulted down-staged
5-yr DFS for stage III patients was worse, while with the        and, consequently, avoided postoperative therapy, under-
updated 2020 edition it was similar to the 7th TNM edition.      going less aggressive surgery (transoral rather than major
To better understand this survival trend, we analysed equal,     surgery). This is because the involvement of the posterior
up-and-down-staging cases. We observed that patients             third of the mobile tongue generally corresponds to pT4a
who changed stage showed better OS and DFS according             due to the invasion of hyoglossus muscle, according to the
to the 2017 and 2020 TNMs. Tirelli et al. reported that          7th TNM edition. At this level, the intrinsic muscles thick-
the 7th edition of the TNM classification seemed to fail         ness is less than 1 cm. The extrinsic muscles are more eas-
prognosis prediction in patients with similar stages and
                                                                 ily infiltrated, and thus considering DOI, tumours involving
treatments due to its unprecise potential of prognosis 19.
                                                                 the hyoglossus muscle can be now restaged as pT1 or pT2,
Furthermore, the 7th TNM edition underestimates 5-yr OS
                                                                 according to the 8th edition.
and 5-yr DFS in advanced stages (stage III and IV), with a
                                                                 The 8th edition has better re-defined the prognostic role of
worse prognosis according to the new 8th edition. This data
                                                                 ECE, which remains the most important factor that influ-
confirms that the 2020 updated staging system improves
                                                                 ences the tumour’s natural history and the patients’ surviv-
survival perspectives due to better risk stratification.
                                                                 al. Mattavelli et al. recently suggested that a single nodal
According to the 2017 8th TNM, neoplasms that invade
                                                                 metastasis with ENE was not significantly associated with
through the cortical bone of the mandible or maxilla, in-
volve the maxillary sinus, or invade the skin of the face,       poor prognosis compared to multiple ENE metastases 17. In
were pT4a 11. The updated 2020 TNM version defines pT4a          our study, according to ENE+, up-staging N occurred in 57
as neoplasms with a maximum dimension > 4 cm and DOI             cases (20%) that were already treated with CRT for ECE,
> 10 mm, in addition to invasion of adjacent soft and bone       also according to the 7th edition. Nodal migration according
tissues 9.                                                       to ECE did not cause a change in adjuvant treatment indica-
The inclusion of the tridimensional parameter to define the      tions since it was a factor that was already considered.
new pT4a and pT3 allows more precise and homogenous              Thus, the uniformity of indications for postoperative thera-
staging, overcoming the limitations of the previous TNM          pies did not seem to be influenced by the T migration of
systems due to underestimation of pT3 with the 7th edition       the TNM system, since the final pathological staging is im-
and pT4a with the 2017 8th TNM, without considering DOI          pacted by the status of N in the case of ECE+ 20.
and size of tumour.                                              Finally, as already published, multivariate analysis con-
The updated 8th TNM HR in DFS revealed midrange val-             firmed a significant role of age in this specific group of pa-
ues between the 7th and the previous 8th TNM. These data         tients 21,22.
reflect the effort of the updated TNM to more precisely pre-     Our study has some limitations such as its retrospective de-
dict prognosis for IVa stage through definition of pT3 and       sign, and some DOI values were reviewed retrospectively
pT4a in terms of tumour size and DOI. According to the           using an assumption concerning extrinsic muscle infiltra-
8th TNM edition, OS for stage IV patients is burdened by         tion 15. However, as far as we know, this is the first paper on
a 5-fold greater risk of death compared to stage I, while,       a large cohort of patients uniformly affected by a specific
when considering the DFS, stage IV had a 3-fold higher           subsite (mobile tongue cancer) that has investigated the
risk of relapse, or second primary, compared to patients in      performance of the 7th and the last two TNM editions (8th
stage I.                                                         edition 2017-2020).



148
                                                                                         Oral cancer: prognostic changes according to the 2020 TNM edition




Conclusions                                                                    6
                                                                                    Pentenero M, Gandolfo S, Carrozzo M. Importance of tumor thick-
                                                                                    ness and depth of invasion in nodal involvement and prognosis of
This study highlights how the new classification of the TNM                         oral squamous cell carcinoma: a review of the literature. Head Neck
(2020) more specifically defines prognosis of patients with                         2005;27:1080-1091. https://doi.org/10.1002/hed.20275
OTSCC according to stage, increasing the risk of death and
                                                                               7
                                                                                    Fukano H, Matsuura H, Hasegawa Y, et al. Depth of invasion as a
                                                                                    predictive factor for cervical lymph node metastasis in tongue car-
disease for the most advanced stages compared to previous                           cinoma. Head Neck 1997;19:205-210. https://doi.org/10.1002/
staging systems (8th 2017 and 7th edition).                                         (sici)1097-0347(199705)19:3<205::aid-hed7>3.0.co;2-6
Further prospective evaluations are recommended to define                      8
                                                                                    American Joint Committee on Cancer. AJCC cancer staging hand-
the most accurate pre-operative methods to detect DOI and                           book. 7th edition. New York: Springer Verlag; 2010.
lymph node status, factors that determine the type of surgi-                   9
                                                                                    Brierley J, Gospodarowicz M, Wittekind C. UICC 8th edition errata –
                                                                                    6th of October 2020. https://www.uicc.org/resources/tnm/publica-
cal resection and adjuvant therapies, and which influence
                                                                                    tions-resources. Updated 2020. Accessed February 2022.
prognosis.                                                                     10
                                                                                    Lydiatt WM, Patel SG, O’Sullivan B, et al. Head and neck cancers-
                                                                                    major changes in the American Joint Committee on cancer eighth
Conflict of interest statement                                                      edition cancer staging manual. CA Cancer J Clin 2017;67:122-137.
The authors declare no conflict of interest.                                        https://doi.org/10.3322/caac.21389
                                                                               11
                                                                                    Amin, MB, Edge, SB, Greene, FL, et al., eds. AJCC cancer staging
                                                                                    manual. 8th ed. New York: Springer; 2017
Funding
                                                                               12
                                                                                    Matos LL, Dedivitis RA, Kulcsar MAV, et al. External validation of
This work was partially supported by the Italian Ministry                           the AJCC cancer staging manual, 8th edition, in an independent co-
of Health with Ricerca Corrente and 5x1000 funds.                                   hort of oral cancer patients. Oral Oncol 2017;71:47-53. https://doi.
                                                                                    org/10.1016/j.oraloncology.2017.05.020
Authors’ contributions                                                         13
                                                                                    Tagliabue M, Gandini S, Maffini F, et al. The role of the T-N tract
Conceptualisation: MA. Data curation: DS, RAM and FC.                               in advanced stage tongue cancer. Head Neck 2019;41:2756-2767.
                                                                                    https://doi.org/10.1002/hed.25761
Formal analysis: SG and PB. Writing – original draft: MT                       14
                                                                                    Kukreja P, Parekh D, Roy P. Practical challenges in measurement
and RDB. Writing – review and editing: RB, SR, GG and                               of depth of invasion in oral squamous cell carcinoma: pictographi-
FM.                                                                                 cal documentation to improve consistency of reporting per the AJCC
                                                                                    8th edition recommendations. Head Neck Pathol 2020;14:419-427.
Ethical consideration                                                               https://doi.org/10.1007/s12105-019-01047-9
This study was approved by the Institutional Ethics Com-
                                                                               15
                                                                                    Piazza C, Montalto N, Paderno A, et al. Is it time to incorporate ‘depth
                                                                                    of infiltration’ in the T staging of oral tongue and floor of mouth can-
mittee (IEO code ethical committee: IEO 225).                                       cer? Curr Opin Otolaryngol Head Neck Surg 2014;22:81-89. https://
The research was conducted ethically, with all study pro-                           doi.org/10.1097/MOO.0000000000000038
cedures being performed in accordance with the require-                        16
                                                                                    R foundation for statistical computing Vienna, Austria. https://www.r-
ments of the World Medical Association’s Declaration of                             project.org/foundation/. Accessed February 2022.
Helsinki.                                                                      17
                                                                                    Mattavelli D, Ferrari M, Taboni S, et al. The 8th TNM classification for
Written informed consent was obtained from all patients.                            oral squamous cell carcinoma: What is gained, what is lost, and what
                                                                                    is missing. Oral Oncol 2020;111:104937. https://doi.org/10.1016/j.
                                                                                    oraloncology.2020.104937
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