10.14639/0392-100X-N1601
Objective. The prognostic significance of the resection margins is still subject of conflicting opinions. The purpose of this paper is to report the results of a study on the margins in carcinoma of the oral cavity, oro-hypopharynx and larynx. Methods. A multicentre prospective study was carried out between 2015 and 2018 with the participation of 10 Italian reference hospitals. The primary objective was to evaluate local control in patients with well-defined clinical characteristics and comprehensive histopathological information.Results. During the study period, 455 patients were enrolled; the minimum follow-up was 2 years. Previous treatment, grading and fresh specimen examination were identified as risk factors for local control in multivariate analysis. On the basis of these results, it seems possible to delineate “risk profiles” for different oncological outcomes.Discussion. The prognostic significance of the margins is reduced, and other risk factors emerge, which require diversified treatment and follow-up.Conclusions. Multidisciplinary treatment with adjuvant therapy, if indicated, reduces the prognostic importance of margins. Collaboration with a pathologist is an additional favourable prognostic factor and quality indicator. An appendix with literature review is present in the online version.
text/xml
1827-675X
1601
en
Emanuela Vaccher
http://creativecommons.org/licenses/by-nc-nd/4.0
ACTA Otorhinolaryngologica Italica
oral-pharyngeal-laryngeal cancer
Multicentre study on resection margins in carcinoma of the oral cavity, oro-hypopharynx and larynx
Text.Serial.Journal
https://www.actaitalica.it/
42
Head and neck
2022-05-16
2021-04-04
2022-05-23
2022-05-23
126-139
1
Emanuela Vaccher
2022/05/16
10.14639/0392-100X-N1601
126
Department of Medical Oncology, CRO Aviano, Pordenone, Italy
1827-675X
oral-pharyngeal-laryngeal cancer
139
Multicentre study on resection margins in carcinoma of the oral cavity, oro-hypopharynx and larynx
https://www.actaitalica.it/article/download/1601/757
42
ACTA OTORHINOLARYNGOLOGICA ITALICA 2022;42:126-139; doi: 10.14639/0392-100X-N1601




Head and neck


Multicentre study on resection margins in carcinoma
of the oral cavity, oro-hypopharynx and larynx
Studio multicentrico sui margini di resezione nel carcinoma del cavo orale, faringe
e laringe
Luigi Barzan1, Cristina Montomoli2, Roberto Di Carlo3, Martina Bertinazzi3, Roberta Colangeli3, Alessandro Martini3,
Piero Nicolai3, Elena Gaio4, Riccardo Artico4, Valentina Lupato5, Vittorio Giacomarra5, Francesca Boscolo Nata6,
Giancarlo Tirelli6, Lucia Lora7, Doriano Politi7, Roberto Spinato7, Anna Menegaldo8, Paolo Boscolo Rizzo8,
Maria Cristina Da Mosto8, Francesco Fiorino9, Irene Herman10, Marco Benazzo10, Alessandro La Boria11,
Cesare Grandi11, Giuseppe Fanetti12, Gianni Franchin12, Vincenzo Canzonieri13, Sandro Sulfaro14, Guido Mazzoleni15,
Emanuela Vaccher16
1
  prev. Head & Neck Surgery, Oncology Referral Center-CRO, Aviano, Pordenone, Italy; 2 Department of Public Health, Experimental
and Forensic Medicine, University of Pavia, Italy; 3 ENT Clinic, University of Padua, Italy; 4 ENT Department, Hospital of Cittadella,
Padua, Italy; 5 ENT Dept, Hospital of Pordenone, Italy; 6 ENT Clinic, University of Trieste, Italy; 7 ENT Department, Hospital of Mestre-
Venice, Italy; 8 ENT Department, University of Treviso-Padua, Italy; 9 ENT Department, Hospital of Legnago, Verona, Italy; 10 ENT
Clinic, University of Pavia, Italy; 11 ENT Department, Hospital of Trento, Italy; 12 Radiotherapy Unit, CRO Aviano, Pordenone, Italy;
13
   Unit of Pathology, CRO Aviano, Pordenone, Italy; 14 Unit of Pathology, Hospital of Pordenone, Italy, 15 Unit of Pathology, Hospital of
Bolzano, 16 Department of Medical Oncology, CRO Aviano, Pordenone, Italy

SUMMARY
Objective. The prognostic significance of the resection margins is still subject of conflict-
ing opinions. The purpose of this paper is to report the results of a study on the margins in
carcinoma of the oral cavity, oro-hypopharynx and larynx.
Methods. A multicentre prospective study was carried out between 2015 and 2018 with the
participation of 10 Italian reference hospitals. The primary objective was to evaluate local
control in patients with well-defined clinical characteristics and comprehensive histopatho-
logical information.
Results. During the study period, 455 patients were enrolled; the minimum follow-up was
2 years. Previous treatment, grading and fresh specimen examination were identified as risk
                                                                                                   Received: April 4, 2021
factors for local control in multivariate analysis. On the basis of these results, it seems pos-   Accepted: October 27, 2021
sible to delineate “risk profiles” for different oncological outcomes.
Discussion. The prognostic significance of the margins is reduced, and other risk factors
                                                                                                   Correspondence
emerge, which require diversified treatment and follow-up.                                         Luigi Barzan
Conclusions. Multidisciplinary treatment with adjuvant therapy, if indicated, reduces the          via dei Molini 3, 33170 Pordenone, Italy
prognostic importance of margins. Collaboration with a pathologist is an additional favour-        Tel. +39 0434 29720
able prognostic factor and quality indicator.                                                      E-mail: luigibarzan@libero.it
An appendix with literature review is present in the online version.
KEY WORDS: resection margins, oral-pharyngeal-laryngeal cancer                                       How to cite this article: Barzan L, Montomoli
                                                                                                     C, Di Carlo R, et al. Multicentre study on re-
                                                                                                     section margins in carcinoma of the oral cav-
RIASSUNTO                                                                                            ity, oro-hypopharynx and larynx. Acta Otorhi-
Obiettivo. Il significato prognostico dei margini di resezione è ancora oggetto di pareri            nolaryngol Ital 2022;42:126-139. https://doi.
discordanti. Scopo di questo scritto è riportare i risultati di uno studio sui margini nel car-      org/10.14639/0392-100X-N1601
cinoma del cavo orale, oro-ipofaringe e laringe.
Metodi. È stato condotto uno studio prospettico multicentrico con la partecipazione di 10          © Società Italiana di Otorinolaringoiatria
Centri italiani, nel periodo 2015-2018, con l’obiettivo primario di valutare il controllo          e Chirurgia Cervico-Facciale
locale in pazienti con ben determinate caratteristiche cliniche e con disponibilità di esau-
rienti informazioni istopatologiche.                                                                              OPEN ACCESS
Risultati. Nel periodo in studio sono stati arruolati 455 pazienti con un follow-up minimo         This is an open access article distributed in accordance with
di 2 anni. All’analisi multivariata per il controllo locale sono risultati fattori di rischio il   the CC-BY-NC-ND (Creative Commons Attribution-Non-
trattamento precedente, il grading e l’esame a fresco dello specimen. Sulla base dei risultati     Commercial-NoDerivatives 4.0 International) license. The
                                                                                                   article can be used by giving appropriate credit and mentio-
ottenuti è possibile delineare un “profilo di rischio” per tutti i diversi outcomes oncologici.    ning the license, but only for non-commercial purposes and
Discussione. Il significato prognostico dei margini è ridotto, altri fattori emergono come         only in the original version. For further information: https://
profili di rischio, che richiederebbero trattamento e follow-up diversificati.                     creativecommons.org/licenses/by-nc-nd/4.0/deed.en




126
                                                                                                         Multicentric study on resection margins




Conclusioni. Il trattamento multidisciplinare con la terapia adiuvante se indicata, può aver ridimensionato l’importanza prognostica dei mar-
gini. La collaborazione con l’anatomopatologo è fattore prognostico favorevole supplementare ed indicatore di qualità.
Appendice con revisione della letteratura nella versione online.
PAROLE CHIAVE: margini resezione, carcinoma cavo orale-faringe-laringe



Introduction                                                            topathological factors in squamous cell carcinoma of the
                                                                        oral cavity, oro-hypopharynx, larynx” was shared and for-
In head and neck squamous cell carcinoma, the variable
                                                                        malised. The primary objective was evaluation of margins
“surgical margins” is often recognised to have a good prog-
                                                                        and other factors in local control (LC), measured by the
nostic relevance 1-3, which involves the indication for thera-
                                                                        absence of relapses at the primary tumour site (T).
peutic intensification 4. However, there are some conflicting
                                                                        Inclusion criteria were: female and male patients who had
opinions, albeit on selected series 5, and reports on the diffi-
                                                                        signed an informed consent, age > 18 years with squa-
culties in standardising data. Namely, quantification of mar-
                                                                        mous cell carcinoma of the oral cavity-oropharynx-larynx-
gins and subdivision into “free”, “close” and “infiltrated”
                                                                        hypopharynx (diagnosis on the surgical specimen) even
do not always have shared values and studies comparing
                                                                        pretreated, surgery performed for radical purposes, ECOG
margin width with relapses have yielded conflicting results.
                                                                        (Eastern Cooperative Oncology Group) performance status
The importance not only of millimeters, but of the margin
                                                                        < 4 and complete staging with adequate imaging.
type and many other factors are recognised 6-9. Although
                                                                        The exclusion criteria were: distant metastatic disease, pal-
margins < 5 mm appear to be associated with a significant-
                                                                        liative surgery, surgical specimen without a correct, definite
ly higher relapse rate and would therefore require adjuvant
                                                                        identification of its anatomical relationships and margins,
treatment 10, data for 20% of local relapses with margins
                                                                        comorbidity so as to discourage the use of adjuvant-con-
≥ 5 mm 11 and for 9% of relapses with margins ≥ 10 mm 12
                                                                        comitant chemotherapy with radiotherapy if indicated,
suggest the presence of subsets of patients who should be
                                                                        pregnancy, lactation, other synchronous tumours (exclud-
adequately identified. Only some studies present multivari-
                                                                        ing cutaneous basal cell carcinoma and cervical Tis) and
ate analysis of prognostic factors without confounding ef-
fects and the interrelation between margins and other his-              primary and secondary immunosuppression.
topathological and clinical factors is still unclear. There is          Consecutively treated patients who had given their consent
also a need for reliable reassessment of the prognostic im-             participated in the study. Type of surgery and any adjuvant
pact of variable “margins” in relation to other parameters              treatment were left to the decisions of the individual cen-
and for accurate identification of patients at risk of relapse          tres, which all had an operative Multidisciplinary Head &
even with free margins. A verification of the relationships             Neck Board.
between all tumour pathologies and size of margins and,
therefore, of the efficacy of surgery as initial or only treat-         Surgery
ment 13,14 is also needed. A prospective multicentre study              The practice of removing margins and sending them sepa-
on resection margins and other factors in squamous cell                 rately was avoided, unless the surgeon saw the need, after
carcinoma of the oral cavity, oro-hypopharynx and larynx                initial resection, for further radicalisation in one or more
was conducted in order to contribute to the clarification of            directions, with correct identification of the side opposite
some of the current issues. This paper aims to present the              to the one of the tumour. If logistically possible, the surgi-
collected data, with a minimum follow-up of 2 years, and                cal specimen was sent intact and fresh to be macroscopi-
review of literature on this topic in the online version.               cally and microscopically evaluated. Alternatively, various
                                                                        measures were taken to make orientation and margins (even
                                                                        of N in the case of massive lymph node metastasis) identifi-
Methods                                                                 able. The surgeon reported the instrument mainly used for
After a series of preliminary meetings of the Directors of              the resection of T, any additional radicalisations, if she/he
the Otolaryngology Departments (the invitation was initial-             decided to stop near an anatomical barrier. If N surgery was
ly extended to the geographical area of Triveneto, North-               performed, it was specified if it was done in monobloc with
Eastern Italy, within the network of the Scuola Triveneta               T, discontinuous or deferred.
di Discipline Otorinolaringoiatriche), with the participation
of Pathologists, Radiotherapists, Medical Oncologists and               Pathology
Biostatistic experts, a protocol of “Multicentre prospective            The modalities of treatment of the specimen, margin map-
observational study on resection margins and other his-                 ping, histopathologic examination and reporting, followed



                                                                                                                                          127
L. Barzan et al.




the guidelines of the Royal College of Pathologists 15, and         only those variables significant at univariate analysis as in-
were reviewed by the Board of Pathologists participating in         dependent variables. In all analyses, p-values < 0.05 were
the study. The evaluation of margins for both intraoperative        considered significant. Stata/IC 15 was used for statistical
and definitive examination was performed with perpendicular         analysis (Stata Corp LP, College Station, TX, USA).
samples (no shave sections) that included T and each margin         All paper documents, enrollment and follow-up forms were
of interest. Each edge was examined at least on 3 floors/levels.    collected and are available for consultation at the Aviano
In the final evaluation of margin distance, which was micro-        Oncological Referral Centre. Data were transferred to an
scopically measured in mm on glass, the specimen’s margins          Excel sheet and regularly updated as the follow-up pro-
were considered. If further immediate or deferred radicalisa-       ceeded.
tions were performed, in the final assessment of margis status
(free or infiltrated) the state of the ultimate definitive margin   Results
was assessed. In the final report, the pathologist, in addition
to the macroscopic and microscopic description of the speci-        Patient enrollment, which began in December 2015, was
men, explained all the items listed in Table III.                   completed in December 2018; all patients had follow-up
                                                                    data. The allocation of the 455 patients in the participating
Radiotherapy                                                        centers was as follows:
Any adjuvant treatment followed the standards of the 2015           • University of Padua: 103;
NCCN guidelines 16. High risk: infiltrated margins, extra-          • Hospital of Cittadella: 77;
capsular lymph nodal spread (ECS), advanced class of T              • Hospital of Pordenone: 71;
or N, lymph nodes at levels IV-V and perineural or angio-           • University of Trieste: 55;
lymphatic spread. Radiation therapy, when possible, started         • Hospital of Mestre-Venezia: 38;
within 6 (max 8) weeks after surgery. The IMRT with a               • University of Padua-Treviso: 38;
dose range between 60 and 66 Gy at the volume of 95%                • Hospital of Legnago: 27;
was used when possible.                                             • University of Pavia: 26;
                                                                    • Hospital of Trento: 11;
Chemotherapy                                                        • Oncology Referral Centre of Aviano: 9.
Only infiltrated margins or ECS indicated concomitant ad-
juvant chemotherapy.                                                General characteristics
                                                                    Table I shows the main clinical characteristics of the study
Statistical analysis                                                population. The mean age at diagnosis was 66.5 (± 12.4)
Descriptive statistics were used to summarise data (mean            years, with a minimum age of 23 and a maximum of 95
and standard deviation, median and interquartile range              years. Table II shows the distribution of smoking status
(IQR) for quantitative variables and frequencies and per-           by sex and by T site. There was a significant association
centages for qualitative ones). Qualitative variables were          between smoking habit and gender (p < 0.0001) and be-
analysed using Pearson’s Chi-square test, while a t-test was        tween smoking habit and tumour site (p < 0.0001): for the
employed to analyse continuous variables.                           most frequent site of T, the oral cavity, the number of never
Univariate [crude ORs and corresponding 95% confidence              smokers was very high compared to smokers and former
intervals (CI)] and multivariate (adjusted ORs and corre-           smokers.
sponding 95% CI) logistic analyses were used to identify            There was no difference between the average daily number
independent risk factors for local control (LC) and loco-           of cigarettes of smokers (18.5 ± 8.8) and the average num-
regional control (LRC).                                             ber of cigarettes smoked by former smokers (20 ± 10.5).
A receiving operating curve (ROC) was plotted for margin            The number of years of smoking was significantly high-
distance against LC status to define a cut-off to maximise          er among smokers vs former smokers (37.8 ± 12.3 vs
sensitivity and specificity.                                        31.5 ± 12.4, p < 0.001).
Kaplan-Meier curves and log-rank test were used for sur-            Table III lists the histopathological characteristics.
vival analysis of local recurrence-free survival (LRFS),            For all T sites, as depth increased by 1 mm, the probabil-
overall survival (OS), disease-specific survival (DSS) and          ity of pN + increased by approximately 5% (OR = 1.05,
disease-free survival (DFS). Multivariate Cox proportional          p = 0.0004, 95% CI 1.02-1.09). If the glottic larynx site is
hazard models were used to determine the independent ef-            excluded, increasing by 1 mm in depth, this increased the
fect of variables on LRFS, OS, DSS and DFS. For each                probability of pN + by 5% (OR = 1.06, p = 0.0005, 95%
outcome, a multivariate Cox model was fitted, including             CI 1.02-1.09).



128
                                                                                               Multicentric study on resection margins




Table I. Clinical characteristics.                               Given the anatomical peculiarities and the different signifi-
                                                  N      %       cance of the margins in mm usually recognised in the litera-
    Sex                Male                       318    69.9    ture, it was decided to keep the analysis of the glottic larynx
                       Female                     137    30.1    separate from the other anatomical sites.
    Site of T          Oral cavity                232    51.0
                       Oropharynx                  62    13.6    LC
                       Supraglottic larynx         40     8.8    LC for T sites other than the glottic larynx
                       Glottic larynx              92    20.2    The number of patients was 363, 300 (83%) with LC and
                       Hypopharynx                 29     6.4    63 (17%) without. Univariate (crude ORs) and multivari-
    cT (clinical class 1                          134    29.5    ate (adjusted ORs) logistic analyses were performed to
    of T)              2                          144    31.6    identify independent risk factors for LC. All variables were
                       3                           88    19.3    analysed, but only those that were significant at univari-
                       4                           89    19.6    ate analysis are reported in Table IV. Namely, at univariate
    cN (clinical class 0                          340    74.7    analysis we can state that:
    of N)              1                           34     7.5    • the probability of LC decreased by about 60% if the pa-
                       2                            1     0.2       tient is pretreated, and more specifically it decreased by
                       2a                          20     4.4       70% if she/he was previously treated by surgery with/
                       2b                          46    10.1       without other therapy, and by about 60% if she/he was
                       2c                          14     3.1       previously treated by radiotherapy with/without other
    TNM stage          I                          125    27.5       therapy (data not shown);
                       II                         116    25.5    • the probability of LC is roughly doubled if the specimen
                       III                         84    18.4       was fresh when it was evaluated;
                       IV                         130    28.6
                                                                 • the probability of LC did not change if the definitive
                                                                    margin was microscopically infiltrated or free. In order
    Previous treatment No                         354    77.8
                                                                    to have a significant probability of LC, it is not only suf-
                       Yes                        101    22.2
                                                                    ficient that the margin is free but it must also be a few
    Surgery of glottic Transoral                   33    35.9
    larynx                                                          mm. The cut-off was 2.3 mm (see forward);
                       Partial laryngectomy        16    17.4
                                                                 • the probability of LC increased by 20% with a 1 mm
                       Total laryngectomy          43    46.7
                                                                    increase in margins;
    Main instrument    Cold                       114    25.1
    (for all T sites)
                                                                 • when passing from one category of grading to the next,
                       Electrosurgical blade      159    34.9
                                                                    the probability of LC was halved;
                       Laser                      112    24.6    • the likelihood of LC decreased by 50% if lymphovascu-
                       Radiofrequencies            10     2.2       lar invasion was present;
                       Energy-based technology*    49    10.8    • the likelihood of LC decreased by approximately 50% if
                       Other                        2     0.4       perineural invasion was present.
                       Missing                      9     2.0    The minimum effective margin in mm for LC at univariate
    Surgery of N       No                         126    27.7    analysis was calculated by using a logistic model contain-
                       Yes selective              253    55.6    ing the nearest microscopic margin on the specimen (mm)
                       Yes all levels              76    16.7    as an independent variable and at ROC analysis a value of
    Type of N surgery En bloc with T              117   25.71    2.3 mm was identified as the LC cut-off (AUC = 0.60, 95%
                       Discontinuous              205   45.05    CI 0.53-0.68, sensitivity 48.33%, specificity 69.84%).
                       Deferred                     5    1.10    The number of positive HPV oropharynx samples (n = 22)
                       Missing                    128   28.13    was too small to determine if the statement is valid even in
Harmonic, Ligasure, EnSeal, Gyrus PK et al.
*
                                                                 this subgroup: “the probability of LC increased by 20% as
                                                                 the margin increases by 1 mm”.
                                                                 At multivariate analysis (Tab. IV), margins (in mm), lym-
The mean values of margins in mm were not modified               phovascular and perineural invasion lose statistical signifi-
within the classes of T (all sites of T, excluding the glottic   cance, whereas the following variables were independent
larynx): more advanced T did not result in wider margins         factors for LC:
on average.                                                      • previous treatment: the probability of LC decreased



                                                                                                                                129
L. Barzan et al.




Table II. Smoking distribution by gender and by T site.
                                  Gender                                                        T site
                              Males      Females            Oral         Oropharynx         Supraglottic         Glottic    Hypopharynx          Total
                                                           cavity                             larynx             larynx
 Smoker                       120           33              69                 19               18                 43             4                  153
 Former smoker                136           26              67                 24               18                 32             21                 162
 Never smoker                  58           75              94                 16                4                 15              4                 133
 Missing                        4            3               2                  3                -                  2              -                  7
 Total                        318           137             232                62               40                 92             29                 455



Table III. Histopathological characteristics.


IIIA. Main characteristics.
                                                                                                                        N                  %
 Fresh specimen evaluation                               No                                                          217                  47.7
                                                         Yes                                                         237                  52.1
                                                         Missing                                                       1                   0.2
 Squamous cell carcinoma                                 Conventional                                                414                  91.0
                                                         Other                                                        37                   8.1
                                                         Missing                                                       4                   0.9
 Grading                                                 Well differentiated                                          72                  15.8
                                                         Moderately differentiated                                   229                  50.3
                                                         Poorly differentiated                                       138                  30.3
                                                         (oropharynx)                                                (30)
                                                         Missing                                                      16                  3.5

                                                  Mean                   SD           Median               IQR              Min                Max
 Depth of invasion (mm)                            9.4                   7.8            8                  4-14              0                  58

                                                                                                                        N                  %
 Growth type                                             Expansive invasive front                                    276                  60.7
                                                         Stellate invasive front                                     143                  31.4
                                                         Tumour satellitosis                                           7                   1.5
                                                         Missing                                                      29                   6.4
 Lymphovascular invasion                                 No                                                          326                  71.7
                                                         Yes, intratumour                                             82                  18.0
                                                         Yes, peritumour                                              42                   9.2
                                                         Missing                                                       5                   1.1
 Perineural invasion                                     No                                                          341                  74.9
                                                         Yes, intratumour                                             70                  15.4
                                                         Yes, peritumour                                              35                   7.7
                                                         Missing                                                       9                   2.0
 p53 (mutated) primary tumour                            Negative                                                     49                  10.8
                                                         Positive                                                     84                  18.4
                                                         Missing                                                     322                  70.8


                                                                                                                                                           ▶



130
                                                                                                      Multicentric study on resection margins




                                                                                                     N                        %
 p53 (mutated) non-infiltrated margins                  Negative                                    108                      23.7
                                                        Positive                                     11                       2.4
                                                        Missing                                     336                      73.9
 HPV                                                    Negative                                    425                      93.4
 (if: p16 pos, and/or hybridisation i.s. High Risk pos, Positive                                     30                       6.6
 and/or genome HPV HR pos)
                                                        (positive oropharynx)                       (22)
                                                        (positive oral cavity)                       (6)
                                                        (positive other sites)                       (2)
 Intratumoural lymphocyte rate infiltrate               Absent                                      181                      39.8
                                                        Present                                     212                      46.6
                                                        Missing                                      62                      13.6
 Perilesional lymphocyte rate infiltrate                Absent or almost absent                     108                      23.7
                                                        Poorly present                              191                      42.0
                                                        Abundantly present                          100                      22.0
                                                        Missing                                      56                      12.3
 Response to previous therapies                         No previous therapies                       363                      79.8
                                                        No vital neoplastic cells                     8                       1.8
                                                        Rare vital neoplastic cells                  22                       4.8
                                                        Neoplastic vital tissue                      11                       2.4
                                                        Missing                                      51                      11.2
 Invaded adjacent structures                            No                                          367                      80.7
                                                        Periosteum                                    5                       1.1
                                                        Bone                                         28                       6.2
                                                        Perichondrium                                 5                       1.1
                                                        Cartilage                                    38                       8.3
                                                        Skin                                          1                       0.2
                                                        Missing                                      11                       2.4
 Moderate/severe adjacent dysplasia                     No                                          331                      72.7
                                                        Yes, moderate, not extended to the margin    29                       6.4
                                                        Yes, moderate, extended to the margin        10                       2.2
                                                        Yes, severe, not extended to the margin      49                      10.8
                                                        Yes, severe, extended to the margin          26                      5.7
                                                        Missing                                      10                      2.2


IIIB. Margins.
 Margin frankly infiltrated into HE sections          No                                            410                      90.1
                                                      Yes                                            40                       8.8
                                                      Missing                                         5                       1.1
 Final margin obtained with                           Initial resection only                        296                      65.1
                                                      Further radicalisations                       143                      31.4
                                                      Deferred radicalisations                       11                       2.4
                                                      Missing                                        5                        1.1
 Microscopic state of definitive margin               Free                                          411                      90.3
                                                      Infiltrated                                   37                       8.1
                                                      Missing                                        7                       1.6
                                                                                                                                          ▶



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L. Barzan et al.




                                                            Mean                  SD             Median          IQR          Min         Max
 Nearest microscopic margin on the specimen (mm)             2.9                  2.2               2            1-5             0          9

                                                                                                                       N              %
 Nearest microscopic margin on the specimen            ≤ 5 mm                                                          287           63.1
                                                       > 5 mm                                                           76           16.7
                                                       Missing (= cases of glottic larynx T)                           92            20.2
 If margin < 5 mm: site (n = 287)                      Superficial mucosa                                              118           41.1
                                                       Submucosa                                                        36           12.5
                                                       Deep soft tissues                                               61            21.2
                                                       Close to anatomic barrier                                        7             2.5
                                                       Bone                                                             2             0.7
                                                       Cartilage                                                        0              0
                                                       Missing                                                          63           22.0
 If margin < 5 mm (n = 287)                            Unifocal                                                        142           49.5
                                                       Multifocal                                                       75           26.1
                                                       Missing                                                          70           24.4
 If margin < 5 mm (n = 287)                            For continuity/contiguity with T                                210           73.2
                                                       For angiolymphatic neoplastic infiltration                       10            3.5
                                                       For perineural infiltration                                       1            0.3
                                                       Missing                                                          66           23.0


IIIC. Lymph node characteristics.
                                                 Mean                   SD               Median            IQR               Min          Max
 No. of identified lymph nodes                   31.6                  21.4                 28            16-45              0            133
 No. of pathologic lymph nodes without           0.97                  1.90                  0             0-1               0             10
 ECS
 No. of pathologic lymph nodes with ECS          0.6                   1.88                  0             0-0               0            19

                                                                                                                       N              %
 Type of extracapsular spread (ECS)                    Focal < 1 mm                                                     21            4.6
                                                       Macro                                                            34            7.5
                                                       Missing                                                         400           87.9
 Resections margin status corresponding to ECS         Positive                                                          6            1.3
                                                       Negative                                                         39            8.6
                                                       Missing                                                         410           90.1
 Levels of pathologic lymph nodes                      Single level, near T                                             58           12.7
                                                       Single level, not near T                                         18            4.0
                                                       Multiple levels                                                 58            12.7
                                                       Missing                                                         321           70.5




                                                                                                                                                ▶



132
                                                                                                      Multicentric study on resection margins




IIID. Staging.
 Pathologic TNM                                                                         N              %
                                       pT                  1                         136              29.9
                                                          1A                         15                3.3
                                                          1B                          2                0.4
                                                           2                         133              29.2
                                                           3                         77               16.9
                                                           4                         15                3.3
                                                          4a                         72               15.8
                                                          4b                          2                0.5
                                                          is                          3                0.7

                                                         N                          %
           pN                         -                  118                       25.9
                                     0                   195                       42.9
                                     1                    52                       11.4
                                     2                     2                       0.45
                                     2a                    4                        0.9
                                     2b                   58                       12.75
                                     2c                   17                        3.7
                                     3                     3                        0.7
                                     3a                    1                        0.2
                                     3b                    5                        1.1


IIIE. Adjuvant treatment.
                                                                                                N                         %
 Radiotherapy                                            No                                     318                      69.9
                                                         Yes, 3D                                 59                      13.0
                                                         Yes, IMRT                               78                      17.1
 Site of radiotherapy (when done, n = 137)               Only T                                 23                       16.8
                                                         Only N                                   6                       4.4
                                                         T+N                                    101                      73.7
                                                         Missing                                  7                       5.1
 Concomitant chemotherapy with RT (when done, n = 137)   No                                      91                      66.4
                                                         Cisplatin alone                         26                      19.0
                                                         Cisplatin + other drugs                  9                       6.6
                                                         Other drugs                              0                        0
                                                         Missing                                 11                       8.0



  by about 60% if the subject was pretreated, more spe-                      increased by 85% if the specimen was evaluated when
  cifically it decreased by 70% if she/he was previously                     fresh.
  treated by surgery with/without other treatments (dif-
  ferent previous treatments are not significant, data not                LC for glottic larynx as T site
  shown);                                                                 92 patients were analysed, among whom 77 (84%) with
• grading: when passing from one grade to the next, the
  probability of LC decreased by 45%;                                     LC and 15 (16%) without. No variables were significantly
• evaluation of fresh specimens: the probability of LC                    associated with LC.



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L. Barzan et al.




Table IV. Local control for T site other than glottic larynx.
                                                                        Crude                                Adjusted
                                                                OR          p       95% CI         OR           p         95% CI
 Previous treatment (No vs Yes)                                 0.36    0.0005     0.20-0.66      0.40        0.006      0.21-0.76
 Fresh specimen evaluation                                       1.9     0.022     1.09-3.35      1.85         0.05      0.99-3.46
 (Yes vs No)
 Nearest microscopic margin on the specimen (mm) as             1.2     0.010      1.04-1.32      1.14        0.084      0.98-1.33
 continuous
 Grading (continuous)                                           0.50    0.0013     0.32-0.76      0.55        0.021      0.33-0.91
 Lymphovascular Invasion                                        0.49     0.013     0.28-0.87      0.85        0.636      0.42-1.69
 (Yes vs No)
 Perineural invasion (Yes vs No)                                0.52    0.032      0.29-0.95      0.73        0.384      0.36-1.49



LRC                                                                    plan-Meier curves for DSS are reported in Figure 2. Previ-
                                                                       ous treatment, frankly infiltrated margin into hematoxylin
LRC for T sites other than glottic larynx
                                                                       & eosin (HE) sections, microscopic state of definitive mar-
363 patients were analysed, among whom 266 (73%) with
                                                                       gins, grade, lymphovascular invasion, cN, perineural inva-
LRC and 97 (27%) without. At multivariate analysis, only
                                                                       sion, TNM stage, cT, pN, pT, pathological nodes with ECS
grade (OR 0.39; p 0.031; 95% CI 0.16-0.91) and p53 sta-
                                                                       and number of pathological lymph nodes were found to be
tus of the primary tumour (pos vs neg) (OR 0.32; p 0.046;
                                                                       prognostic factors for DSS. Table VA shows adjusted HRs
95% CI 0.11-0.98) remained significant. This means that
                                                                       for DSS. Frankly infiltrated margins into HE sections, pT
moving from one grade to the next, the likelihood of LRC
                                                                       and pathological lymph nodes with ECS were prognostic
decreases by approximately 40%, regardless of other vari-
                                                                       factors for DSS in the multivariate Cox model.
ables in the model. Moreover, the probability of LRC de-
creased by 68% if the primary tumour was p53-positive,                 DSS for glottic larynx as the T site
regardless of other variables in the model.                            Median follow-up time was 34.3 (mean 30.7) months. Ka-
                                                                       plan–Meier curves for DSS are reported in Figure 3. Previ-
LRC for glottic larynx as the T site
                                                                       ous treatment, cN, tumour growth, pT and perineural inva-
In the sample of 92 patients, 75 (81.5%) with LRC and 17
                                                                       sion were found to be prognostic factors for DSS for glottic
(18.5%) without, none of the variables were significant.
                                                                       larynx tumours.
                                                                       Table VB shows adjusted HRs for DSS: only cN is a prog-
LRFS
                                                                       nostic factor for DSS. Due to the small sample size, the
LRFS for T sites other than glottic larynx                             95% CI are wide.
Median follow-up time was 30.8 (mean 29.4) months. Ka-
plan-Meier curves are reported in Figure 1. Previous treat-            OS
ment, grading, evaluation of the fresh specimen, micro-
                                                                       OS for T sites other than the glottic larynx
scopic state of definitive margin, lymphovascular invasion,
                                                                       Median follow-up time was 32.8 (mean 31) months. At
perineural invasion, TNM stage, pT and pathologic nodes
                                                                       multivariate analysis (Tab. VA) grade, TNM stage (III-IV
with ECS were found to be prognostic factors for LRFS.
                                                                       vs I-II) and pT (classes 3-4 vs 1-2) were significant prog-
Table VA shows adjusted HRs for LRFS. Pathological
                                                                       nostic factors.
lymph nodes with ECS were the only prognostic factors for
LRFS in a multivariate Cox model.                                      OS for glottic larynx as the T site
                                                                       Median follow-up time was 35.4 (mean 32.8) months. At
LRFS for glottic larynx as the T site
                                                                       multivariate analysis (Tab. VB) depth of invasion, perineural
Median follow-up time was 35 (mean 31.7) months. No
                                                                       invasion, cN (0 vs the remnant), pT (classes 3-4 vs 1-2) and
variables were significantly associated with LC.
                                                                       pN (0 vs the remnant) were significant prognostic factors.
DSS
                                                                       DFS
DSS for T sites other than glottic larynx                              DFS for T sites other than the glottic larynx
Median follow-up time was 29.8 (mean 27.8) months. Ka-                 Median follow-up time was 30 (mean 28) months. In multi-



134
                                                                                                                     Multicentric study on resection margins




                                                                                       variate analysis (Tab. VA), only the number of pathological
                                                                                       lymph nodes with ECS was significant (at least 1 vs none).
                                                                                       DFS for glottic larynx as the T site
                                                                                       Median follow-up time was 34 (mean 30.7) months. At
                                                                                       multivariate analysis (Tab. VB), no variables were signifi-
                                                                                       cantly associated with DFS.

                                                                                       Further results
                                                                                       • There was no association between smoking and a mi-
                                                                                         croscopic definitive margin. There was no association
                                                                                         between smoking and LC and DFS.
                                                                                       • The probability that further radicalisations were per-
                                                                                         formed was 4 times greater if the specimen was evalu-
                                                                                         ated when it is fresh (OR = 4.6, 95% CI 2.73-7.73,
                                                                                         p < 0.0001).
                                                                                       • LC and DFS (all anatomic sites, excluding glottic lar-
                                                                                         ynx) do not change whether, with theoretically inad-
                                                                                         equate surgical radicality (microscopic state of the de-
                                                                                         finitive margin = infiltrate, or margin on the specimen
                                                                                         < 5 mm), adjuvant radiotherapy was performed (96 pa-
                                                                                         tients) or not (191 patients).
                                                                                       • LC and DFS do not change if, with inadequate surgical
                                                                                         radicality, adjuvant radiotherapy was done with ≥ 60 Gy
                                                                                         or less.
                                                                                       • Salvage therapy for T relapse (all T sites) was effective
                                                                                         (no further recurrence) in 18 of 81 patients (22.2%).

                                                                                       Discussion
                                                                                       In the recent literature, the prognostic significance of resec-
                                                                                       tion margins in carcinomas of the upper airways has been
                                                                                       variably evaluated (see Appendix with literature review 2000-
                                                                                       2021 in the online version: https://www.actaitalica.it/article/
                                                                                       view/1601). Some authors have considered that millimetre
                                                                                       distance – albeit with diverse interpretative ranges – is cru-
                                                                                       cial for oncological outcomes 17-19 (among the most recent).
                                                                                       Others, while confirming the importance of margins, also
                                                                                       suggest that other factors affect prognosis 20,21 (among the
                                                                                       most recent). There are also several authors who deny the
                                                                                       prognostic significance of margins 22,23 (among the most re-
                                                                                       cent), even in multivariate analyses 24,25.
                                                                                       The present multicentre study, which systematically em-
                                                                                       ployed multivariate data analysis, shows some unexpected
                                                                                       results, as well as the confirmation of some well-known
                                                                                       prognostic factors.
                                                                                       The prognostic significance of resection margins seems decid-
                                                                                       edly reduced: only the “surgical margin frankly infiltrated into
                                                                                       HE sections” for DSS remained significant, whereas all the
Figure 1. Tumour relapse-free survival (TRFS) for T sites other than glottic larynx.
Kaplan-Meier curves based on: (a) previous treatment; (b) grading; (c) fresh speci-
                                                                                       others “margin items” lost importance, even if they are based
men evaluation; (d) microscopic state of definitive margin; (e) lymphovascular inva-   on the mm variable of the margin distance. Even carrying out
sion; (f) TNM stage; (g) perineural invasion; (h) pT; (i) pathologic nodes with ECS.   further radicalisations was not significant: if the intervention



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L. Barzan et al.




Figure 2. Diseases-pecific survival (DSS) for T site other than glottic larynx. Kaplan-Meier curves based on: (a) previous treatment; (b) frankly infiltrated margin
into HE sections; (c) microscopic state of definitive margin; (d) grading; (e) lymphovascular invasion; (f) perineural invasion; (g) cN; (h) TNM stage; (i) cT; (l) pN;
(m) pT; (n) pathologic nodes with ECS; (o) No. of pathologic lymph nodes.


for some reason was conducted in an inadequate manner with                            tial resection or with subsequent radicalisations. The prob-
a margin of the specimen that was grossly infiltrated at histol-                      ability of LC was about doubled only when the fresh speci-
ogy, the prognosis remained difficult to predict.                                     men was evaluated. This is a surprising, unexpected and not
The variable “fresh specimen evaluation” is not commonly                              easily explainable result. We assume that evaluation of the
considered in most clinical studies on head and neck cancers,                         fresh specimen constitutes a quality indicator of the surgical
probably because it is not considered to be related to onco-                          and pathological procedures and of their effectiveness.
logical outcomes. In the series presented herein, it was deter-                       The seriously unfavourable significance of previous treat-
mined if it was linked to other variables. The probability of                         ment for LC is once again documented in this series, espe-
further radicalisations was four times greater if the specimen                        cially for patients who had previously undergone surgery.
was evaluated when it is fresh, but on LC it was irrelevant                           There must be a full awareness of this when preparing a
whether the definitive margin was obtained only with the ini-                         patient for salvage surgery.



136
                                                                                                                                         Multicentric study on resection margins




Table V. Adjusted hazard ratios for different survival outcomes (only significant HR are reported in the Table).
VA. T site other than glottic larynx.
                                                LRFS                             DSS                             OS                                               DFS
                                                HR           p      95% CI           HR           p      95% CI      HR       p        95% CI         HR         p        95% CI
     Nearest microscopic margin               0.82*     0.057     0.68-1.00
     on the specimen (mm) as
     continuous
     Frankly infiltrated margin HE sect                                             2.26**    0.043     1.02-4.96
     Grading (continuous)                                                                                           1.65^   0.008     1.14-2.40
     TNM stage (III-IV vs I-II)                                                                                     2.79^   0.009     1.29-6.00
     pT (classes 3-4 vs classes 1-2)                                                2.43**    0.017     1.17-5.07   1.91^   0.035     1.05-3.48      1.80°     0.054     0.99-3.27
     Pathologic lymph nodes with ECS           2.3 *
                                                        0.039     1.04-5.08         2.07**    0.046     1.01-4.24                                    2.03°     0.019     1.12-3.66
     (at least 1 vs none)
*
  Adjusted by: previous treatment, fresh specimen evaluation, nearest microscopic margin on the specimen, grading, lymphovascular invasion, perineural invasion, cT, pT.
**
  Adjusted by: previous treatment, nearest microscopic margin on the specimen, depth of invasion, grading, lymphovascular invasion, perineural invasion, cT, cN, pN, identified lymph
nodes, chemotherapy.
^
  Adjusted by: depth of invasion, frankly infiltrated margin HE, nearest microscopic margin on the specimen, lymphovascular invasion, perineural invasion, cT, cN, pN, identified lymph
nodes, pathologic lymph nodes with ECS.
°
  Adjusted by: previous treatment, frankly infiltrated margin HE, nearest microscopic margin on the specimen, grading, lymphovascular invasion, perineural invasion, TNM stage, pN,
identified lymph nodes, number of pathological lymph nodes.

VB. Glottic larynx as T site.
                                                         LRFS                                  DSS                               OS                               DFS
                                              HR         p        95% CI            HR        p         95% CI       HR      p        95% CI          HR         p        95% CI
     Depth of invasion                                                                                              0.83&   0.010 0.72-0.96
     Perineural invasion                                                                                            5.76&   0.025 1.24-26.7
     cN (0 vs remnant)                                                          7.62§        0.007 1.74-33.36       14.7&    0.01 1.87-115.0
     pT (classes 3-4 vs classes 1-2)                                                                                15.6&   0.009 1.97-123.3
     pN (0 vs remnant)                                                                                              6.96&   0.015 1.46-33.11
§
     Adjusted by: previous treatment, depth of invasion, perineural invasion, pT.
&
     Adjusted by: previous treatment, depth of invasion, lymph node invasion.



T class does not appear to be a prognostic factor for LC.                                             was not randomly used but linked to specific prognostically
This is probably due to the effect of radiotherapy, which,                                            unfavourable clinical indications. Even the fact that LC and
since it is administered more frequently in more advanced                                             DFS do not change whether, with theoretically inadequate
T classes, corrected the theoretically worse prognosis,                                               surgical radicality, adjuvant radiotherapy is performed
making it similar to that of the early classes. In fact, pa-                                          or not, does not imply that adjuvant therapy was useless,
tients with more advanced T classes who received adjuvant                                             This means that it is difficult to have meaningful data if
radiotherapy were 63/121 (52%), while those with early                                                the guidelines followed do not provide strict indications:
T classes who received radiotherapy were 56/240 (23%)                                                 the NCCN 16 suggests that “if positive surgical margins
(p < 0.001). A similar consideration on the “leveling” effect                                         are reported, surgical re-resection and/or adjuvant therapy
of adjuvant treatment can be made for all the variables on                                            should be considered in selected patients” (not: must be
resection margins.                                                                                    performed in all patients).
The usefulness of adjuvant treatment on inadequate resec-                                             Histopathological grading, a significant prognosticator,
tion margins has long been debated in literature: one recent                                          is often considered to be a partially subjective, operator-
paper 22, on a series of 1199 patients with head and neck                                             dependent parameter. A cumulative series of 10 centres
carcinoma aged ≥ 70 years, argued that benefits in OS with                                            may help eliminate any subjective bias from this variable.
adjuvant therapy are only observed for N2-3, and not for                                              On the basis of the outcomes achieved, it seems possible to
margins.                                                                                              delineate “risk profiles” for the various oncological results
In the present series, radiotherapy did not emerge as a prog-                                         with the variables found to be significant at multivariate
nostic factor in univariate analyses (and therefore cannot be                                         analyses:
included in Cox’s models for multivariate ones), because it                                           • for T sites other than glottic larynx: previous treatment



                                                                                                                                                                                137
L. Barzan et al.




                                                                                  pharynx, supraglottic larynx) may change the connotation
                                                                                  of some margins; the prognostic value of specimen-driven
                                                                                  or bed-driven frozen sections was not evaluated; molecular
                                                                                  margins were not considered. “Margins” are a “world” and
                                                                                  dealing with this issue in a complete, exhaustive manner in
                                                                                  a single study is perhaps an impossible task. Further pro-
                                                                                  spective well-designed and adequately representative stud-
                                                                                  ies are desirable to compensate for the shortcomings of the
                                                                                  present analysis and to confirm or not what emerged here.

                                                                                  Conclusions
                                                                                  The treatment administered to patients in this series, with
                                                                                  radical surgery and possible adjuvant therapy, significantly
                                                                                  reduced the prognostic importance of resection margins.
                                                                                  The presence of the Multidisciplinary Board, which is ac-
                                                                                  tive in all participating centres, helped to standardise treat-
                                                                                  ments, possibly reducing the theoretical significance of
                                                                                  resection margins. At multivariate analyses, only surgical
                                                                                  margins that frankly infiltrated into the HE sections (for
                                                                                  DSS) remained significant, whereas other factors were not.
                                                                                  There are many other prognostic factors, however, most of
                                                                                  which are well known, which demonstrate that there are
                                                                                  “risk profiles” that are worthy of renewed attention. The
                                                                                  building of an effective collaboration between the surgeon
                                                                                  and pathologist, which also entails the practice of exam-
Figure 3. Disease-specific survival (DSS) for glottic larynx as T site. Kaplan-
Meier curves based on: (a) previous treatment; (b) cN; (c) tumour growth;         ining the fresh specimen, is documented as a favourable
(d) pT; (e) perineural invasion.                                                  prognostic factor and which can be taken as a quality indi-
                                                                                  cator for the degree of efficiency of a given centre.

   (for LC), high grade (for LC, LRC, OS), non-fresh spec-                        Acknowledgements
   imen evaluation (for LC), ECS (for LRFS, DFS, DSS),                            The authors wish to acknowledge the Scuola Triveneta di
   frankly infiltrated surgical margin into HE sections (for                      Discipline Otorinolaringoiatriche and its President Prof.
   DSS), p53 on T (for LRC), advanced stage (for OS), ad-                         Roberto Spinato, who made the organisation of this study
   vanced pT (for OS, DSS), all represent clear risk factors;                     possible.
• for glottic larynx as the T site: cN positive class (for DSS                    Special thanks to Mrs. Daniela Michilin (Radiotherapy,
   and OS), depth of invasion, advanced pT, the pN positive                       CRO Aviano) for secretarial support and to Manuela Anelli,
   class, perineural invasion (for OS) and advanced TNM                           PhD for external English language revision.
   stage (for DSS) were documented as risk factors.
All these factors are associated with prognostic risk, which                      Conflict of interest statement
is different depending on the outcome considered, but                             The authors declare no conflict of interest.
which would require diversified treatment if possible or, at
least, closer and more complete follow-up.                                        Funding
Certainly some aspects of this study could have been im-                          This research did not receive any specific grant from fund-
proved: although the large number of patients constitutes a                       ing agencies in the public, commercial, or not-for-profit
key factor for statistical significance of the analysis, it can-                  sectors.
not be excluded that the combination of different anatomi-
cal sites and sub-sites and the non-stringent common guide-                       Authors’ contributions
lines followed for adjuvant therapy may have produced                             All authors had full access to the data in the study and take
some weakness. Furthermore, it was not considered that the                        responsability for the integrity of the data and the accuracy
concept of compartment surgery (oral tongue, lateral oro-                         of the data analysis. Study concept and design: LB, RDC,



138
                                                                                                                    Multicentric study on resection margins




AM, RA, VG, GT, DP, RS, PBR, MCDM, FF, CG, GF, VC,                            10
                                                                                   Anderson CR, Sisson K, Moncrieff M. A meta-analysis of margin
                                                                                   size and local recurrence in oral squamous cell carcinoma. Oral Oncol
SS, GM, EV. Acquisition of data: LB, RDC, MB, RC, PN,
                                                                                   2015;51:464-469. https://doi.org/10.1016/j.oraloncology.2015.01.015
EG, VL, FBN, LL, DP, AM, FF, IH, MB, ALB, GF. Analy-                          11
                                                                                   Brandwein-Gensler M, Teixeira MS, Lewis CM, et al. Oral squa-
sis of data: CM. Drafting the manuscript: LB, CM. Critical                         mous cell carcinoma. Histologic risk assessment, but not margin
revision of the manuscript for intellectual content: LB, CM,                       status, is strongly predictive of local disease-free and overall sur-
                                                                                   vival. Am J Surg Pathol 2005;29:167-178. https://doi.org/10.1097/01.
GF. Study supervision: LB.
                                                                                   pas.0000149687.90710.21
                                                                              12
                                                                                   Hicks WL, North JH, Loree TR, et al. Surgery as a single modality ther-
Ethical consideration                                                              apy for squamous cell carcinoma of the oral tongue. Am J Otolaryngol
This study obtained the approval from the Independent Eth-                         1998;19:24-28. https://doi.org/10.1016/s0196-0709(98)90061-8
ics Committee of the Oncology Referral Centre of Aviano,                      13
                                                                                   Upile T, Fisher C, Jerjes W, et al. The uncertainty of the surgical mar-
                                                                                   gin in the treatment of head and neck cancer. Oral Oncol 2007;43:321-
Pordenone, Italy (19 October 2015, CRO-2015-43) and
                                                                                   326. https://doi.org/10.1016/j.oraloncology.2006.08.002
subsequently from the Ethics Committees of all participat-                    14
                                                                                   Dik EA, Willems SM, Ipenburg NA, et al. Resection of early oral
ing centres.                                                                       squamous cell carcinoma with positive or close marginas: relevance of
The research was conducted ethically, with all study pro-                          adjuvant treatment in relation to local recurrence. Margin of 3 mm as
                                                                                   safe as 5 mm. Oral Oncol 2014;50:611-615. https://doi.org/10.1016/j.
cedures being performed in accordance with the require-
                                                                                   oraloncology.2014.02.014
ments of the World Medical Association’s Declaration of                       15
                                                                                   Helliwell T, Woolgar JA. Standard and minimum datasets for report-
Helsinki.                                                                          ing cancers. Dataset for histopathology reporting of mucosal malig-
Written informed consent was obtained from each partici-                           nancies of the head and neck. London: Royal College of Pathologist
                                                                                   2011 (https://www.rcpath.org/profession/guidelines.html).
pant/patient for study participation and data publication.
                                                                              16
                                                                                   NCCN Guidelines, Head Neck Cancers, Version 1.2015 (www.nccn.
                                                                                   org/professionals).
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