10.14639/0392-100X-N1653
Introduction. Numerous studies have evaluated the prognostic significance of perineural invasion (PNI) in oral cancer; however, the results are inconclusive. Purpose. To identify the prognostic value of PNI in oral cancer through a metanalysis. Methods. A literature review was carried out, searching the MedLine databases via Pubmed, Scielo, Lilacs, Cochrane and Websco. Results. A total of 56 studies were included. The results indicate that PNI in oral cancer has an incidence of 28% (95% confidence interval (CI) 24-31%); 5-year survival with relative risk (RR) 0.67 (0.59-0.75); 5-year disease-free survival RR 0.71 (0.68-0.75); locoregional recurrence with RR 2.09 (1.86-2.35). Conclusions. PNI is a negative prognostic factor in oral cancer.
text/xml
1827-675X
1653
en
Debora Modelli Vianna Ocampo Quintana
http://creativecommons.org/licenses/by-nc-nd/4.0
ACTA Otorhinolaryngologica Italica
systematic review
Prognostic impact of perineural invasion in oral cancer: a systematic review
Text.Serial.Journal
https://www.actaitalica.it/
42
Reviews
2022-03-07
2021-04-30
2022-03-07
2022-03-07
17-25
1
Luiz Paulo Kowalski
2022/03/07
10.14639/0392-100X-N1653
17
Head of the Department of Head and Neck Surgery, Hospital das Clinicas, University of Sao Paulo School of Medicine, Sao Paulo, Brazil
1827-675X
systematic review
25
Prognostic impact of perineural invasion in oral cancer: a systematic review
https://www.actaitalica.it/article/download/1653/737
42
ACTA OTORHINOLARYNGOLOGICA ITALICA 2022;42:17-25; doi: 10.14639/0392-100X-N1653




Review


Prognostic impact of perineural invasion in oral
cancer: a systematic review
Impatto prognostico dell’invasione perineurale nel cancro orale:
una revisione sistematica
Debora Modelli Vianna Ocampo Quintana1, Rogerio Aparecido Dedivitis2, Luiz Paulo Kowalski3
1
 Department of Head and Neck Surgery, Hospital Heliopolis, São Paulo, Brazil; 2 Department of Head and Neck Surgery, Hospital
das Clinicas, University of São Paulo School of Medicine, São Paulo, Brazil; 3 Head of the Department of Head and Neck Surgery,
Hospital das Clinicas, University of São Paulo School of Medicine, São Paulo, Brazil


SUMMARY
Introduction. Numerous studies have evaluated the prognostic significance of perineural
invasion (PNI) in oral cancer; however, the results are inconclusive.
Purpose. To identify the prognostic value of PNI in oral cancer through a metanalysis.
Methods. A literature review was carried out, searching the MedLine databases via Pub-
med, Scielo, Lilacs, Cochrane and Websco.
Results. A total of 56 studies were included. The results indicate that PNI in oral cancer has
an incidence of 28% (95% confidence interval (CI) 24-31%); 5-year survival with relative
risk (RR) 0.67 (0.59-0.75); 5-year disease-free survival RR 0.71 (0.68-0.75); locoregional
recurrence with RR 2.09 (1.86-2.35).
Conclusions. PNI is a negative prognostic factor in oral cancer.
KEY WORDS: oral cancer, carcinoma, squamous cell, perineural invasion, prognosis, risk
factors, metanalysis, systematic review

RIASSUNTO
Introduzione. Numerosi studi hanno valutato il significato prognostico dell’invasione peri-
neurale (PNI) nel cancro orale; tuttavia, i risultati sono inconcludenti.                        Received: April 30, 2021
Scopo. Identificare il valore prognostico della PNI nel cancro orale attraverso una meta-        Accepted: November 21, 2021
nalisi.
Metodi. È stata effettuata una revisione della letteratura, sfruttando MedLine Pubmed,           Correspondence
Scielo, Lilacs, Cochrane e Websco.                                                               Debora Modelli Vianna Ocampo Quintana
Risultati. Sono stati inclusi un totale di 56 studi sul cancro orale. I risultati indicano che   Rua Meruoca 108 Jd. Vila Mariana CEP: 01547-
la PNI nel cancro orale ha un’incidenza del 28% (95% Confidence Interval (CI) 24-31%);           150, São Paulo, Brazil.
Sopravvivenza a 5 anni con rischio relativo (RR) 0,67 (0,59-0,75); sopravvivenza libera          Tel. +55 1121931213
da malattia a 5 anni RR 0,71 (0,68-0,75); recidiva locoregionale con RR 2,09 (1,86-2,35).        E-mail: dr.deboravianna@gmail.com
Conclusioni. La PNI è un fattore prognostico negativo nel cancro orale.
PAROLE CHIAVE: cancro orale, carcinoma, cellule squamose, invasione perineurale,                   How to cite this article: Quintana DMVO, De-
                                                                                                   divitis RA, Kowalski LP. Prognostic impact of
prognosi, fattori di rischio, metanalisi, revisione sistematica                                    perineural invasion in oral cancer: a systematic
                                                                                                   review. Acta Otorhinolaryngol Ital 2022;42:17-
                                                                                                   25. https://doi.org/10.14639/0392-100X-N1653

Introduction                                                                                     © Società Italiana di Otorinolaringoiatria
                                                                                                 e Chirurgia Cervico-Facciale
Among head and neck tumours, lesions of the upper aerodigestive tract stand
out, of which 40% are oral cavity tumours 1,2. Approximately 95% of these are                                   OPEN ACCESS
squamous cell carcinoma (SCC) 3,4. SEER 5 data (Surveillance, Epidemiology                       This is an open access article distributed in accordance with
                                                                                                 the CC-BY-NC-ND (Creative Commons Attribution-Non-
and End Results Program) indicate that the estimated incidence of oral cancer                    Commercial-NoDerivatives 4.0 International) license. The
for 2020 is 53,260 new cases in the USA (2.9%), with 10750 estimated deaths                      article can be used by giving appropriate credit and mentio-
                                                                                                 ning the license, but only for non-commercial purposes and
(1.8%). Its mortality in the period from 2013 to 2017 was 2.5/100,000. Over                      only in the original version. For further information: https://
the past 20 years it has remained stable in terms of incidence and mortality.                    creativecommons.org/licenses/by-nc-nd/4.0/deed.en




                                                                                                                                                           17
D.M.V.O. Quintana et al.




The prognosis of oral cavity cancer patients depends main-           Studies where there was no analytical distinction among
ly on the size of the lesion, level of local invasion, regional      the multiple sites of primary disease, non-surgical treat-
lymphatic dissemination and presence of distant metasta-             ment, studies that primarily evaluated surgical technique,
ses 6; other predictive factors are race, sex, vascular embo-        studies evaluating a specific head and neck cancer popula-
lisation, perineural invasion (PNI) and histological grade 7.        tion, duplicate studies or studies with replicated series, in
However, SCC is not the most marked tendency to PNI,                 vitro studies, and those that primarily assessed toxicity or
such as, for example, adenoid cystic carcinoma. Assess-              quality of life were excluded.
ment of prognostic factors acts as a guide for treatment and         Outcomes were treated as categorical and analysed with
follow-up decisions 8.                                               relative risk (RR) including 95% confidence interval (95%
PNI is a process predominantly characterised by neoplasm             CI). Significant heterogeneity (occurs when different stud-
invasion of the nerves, which can occur in the absence of            ies have different designs, for example) was defined as I2
lymphatic or vascular invasion. Its propagation does not oc-         > 50%. A random effect model was used, except when sta-
cur through lymphatic dissemination, but through molecu-             tistical heterogeneity was not significant. The funnel plot
lar mediators that guide these cells through neural invasion.        was used to assess heterogeneity. Analyzes developed in
PNI was first described in head and neck cancer by Cruvei-           RevMan 5.4 and R software, in the “Meta-Analysis” pack-
heir 9 in 1835, being defined more than a century later as the       age.
invasion of one of the three nerve layers or the involvement
of at least one third of its circumference 10. Its incidence         Results
varies from 2 to 30%, with some reports of 82%. Such vari-
ation occurs when there are studies that specifically study          A total of 112 studies were retrieved; after reading all the
PNI and studies where PNI is an evaluated cofactor, as well          articles, 56 studies potentially eligible for inclusion in the
as discrepancies when there is a slide review with an active         review were selected.
search for PNI 11.                                                   The incidence of PNI ranged between 3.35 and 63.15%.
The growth patterns of PNI are diverse, and can occur as: in-        The risk of bias was assessed using the Cochrane scale,
traneural invasion, increasing formation, circular formation         which highly value blinding. Through this scale, we identi-
and onion-peel formation 12. Neoplastic cells tend to be con-        fied a high potential for bias. In our study, the combined
centrated in the perineurium, which is hypovascularised, and         incidence of PNI in oral cavity SCC, using the random ef-
can extend up to 12 cm beyond the surgical margin through            fect, was 28% (Fig. 1).
skip lesions 13. Tumour growth via the neural pathway can            Of the total 5969 patients evaluated for overall 5-year sur-
occur in two ways: i) perineural invasion, usually in the            vival, the RR was 0.67 (95% CI 0.64-0.74), with a high rate
small nerves, identified under microscopy; invasion of minor         of heterogeneity when assessing the fixed model, so that
nerves is associated with an increased risk of local recur-          the random evaluation model was used, with RR 0.67 (95%
rence and cervical metastases, and is a predictor of survival,       CI 0.59-0.75) (Fig. 2). The funnel plot shows publication
regardless of the risk of capsular rupture 14; ii) perineural dis-   bias regarding overall survival (Fig. 3).
semination, where there is gross invasion of the nerve.              Regarding disease-free survival at 5 years, the outcome was
The purpose of this study is to analyse the prognostic im-           binary (recurrence/total number of subjects observed in the
pact of PNI in oral cancer patients through a systematic             study). A total of 5508 patients were evaluated; the RR was
review, regarding locoregional recurrence, disease-free sur-         0.71 (95% CI 0.68-0.75), with low heterogeneity (Fig. 4).
vival and mortality.                                                 Publication bias was also identified (Fig. 5).
                                                                     As for locoregional recurrence, a total of 2593 patients
Methods                                                              were evaluated; the RR was 2.09 (95% CI 1.86-2.35), with
                                                                     a high heterogeneity rate when assessing the fixed mod-
Studies that evaluated PNI in patients with oral cavity SCC          el. For evaluation of the random model, the RR was 2.2
were included. There was no restriction on the study de-             (95% CI 1.6-3.01) (Fig. 6). Publication bias was identified
sign, year of publication; all articles in English, Spanish          (Fig. 7).
and Portuguese were reviewed. Overall survival, disease-
free survival, and locoregional recurrence were evaluat-
ed. The MedLine databases were consulted via Pubmed,
                                                                     Discussion
Scielo, Lilacs, Cochrane and Websco, with the keywords:              The search for prognostic factors serves the purpose of bet-
“mouth cancer” OR “oral cancer” AND “perineural inva-                ter understanding the natural history of cancer, prediction
sion” AND “prognosis”.                                               of therapeutic interventions, identification of homogeneous



18
                                                                               Prognostic impact of perineural invasion in oral cancer: a systematic review




Figure 1. Combined incidence of PNI using a random effect model. An incidence of 28% was identified.



                                                                                                                                                       19
D.M.V.O. Quintana et al.




Figure 2. Meta-analysis of 5-year survival using a model with a random effect.


                                                                                 One of the limitations in the literature about PNI is the lack
                                                                                 of standardisation or method for its detection. Despite the
                                                                                 definition disseminated by Liebig et al. 15, many authors use
                                                                                 broader definitions, with PNI being contact of the nerve
                                                                                 with neoplastic cells. Thus, studies of similar methodolo-
                                                                                 gies, with similar populations, tend to have different results,
                                                                                 since they start from a different principle of PNI, justifying
                                                                                 the combined incidence of PNI in oral cancer ranging from
                                                                                 3.35 to 63.15% in our study.
                                                                                 Furthermore, the technique used to detect PNI in studies is
                                                                                 not standardised. Most pathologists report PNI as present
                                                                                 or absent, without specifying the location, extent, or size
                                                                                 of the nerve involved, which is not enough to identify char-
                                                                                 acteristics that may actually cause a change in the impact
Figure 3. Funnel plot of the 5-year survival meta-analysis, indicating pub-      of the disease (the simple contact of the nerve with tumour
lication bias.                                                                   cells does not worsen prognosis; however, multiple foci of
                                                                                 invasion lead to increased local recurrence) 16.
groups of patients, comparison of results of different treat-                    Thus, there is difficulty in diagnosing PNI. A false-negative
ments, identification of groups with unfavorable evolution                       result can occur in biopsies 17, more frequently when pa-
and planning of follow-up strategies. It also allows for indi-                   thologists are not specifically looking for PNI. Thus, mo-
vidualisation of treatment, with more aggressive strategies                      lecular studies are being carried out in order to facilitate
in groups with adverse variables and deintensification of                        the detection of PNI 18; the expression of N-CAM demon-
treatment to those with more favourable variables 15.                            strates a relation with the presence of PNI 19, but it is not yet



20
                                                                                  Prognostic impact of perineural invasion in oral cancer: a systematic review




Figure 4. 5-year disease free-survival meta-analysis using a fixed effect model. Low heterogeneity.


                                                                                 large calibre nerves, when it is possible to identify bone
                                                                                 erosion, enlargement of the foramina of the skull base,
                                                                                 loss of fat in the pterygopalatine fossa and oedema in the
                                                                                 nerve 20.
                                                                                 Neural involvement usually starts with branches smaller
                                                                                 than 1 mm, progressing to larger ones. When PNI is present,
                                                                                 the surgical margins are no longer controlled by surgery,
                                                                                 since tumour progression can occur up to 10 cm beyond its
                                                                                 point of origin. Tumour cells tend to be concentrated in the
                                                                                 perineurium, a poorly vascularised and relatively hypoxic
                                                                                 environment, which leads to a relative radio resistance, cor-
                                                                                 roborating the worst prognosis 14 of PNI.
                                                                                 PNI is associated with an increased risk of lymph node me-
                                                                                 tastases. The presence of PNI is related to the expression of
Figure 5. Funnel plot of the 5-year disease free-survival meta-analysis, in-     cortactin (a protein that has been suggested that affects the
dicating publication bias.                                                       overall aggressiveness of head and neck carcinomas), as
                                                                                 well as the presence of lymph node metastasis; it is inferred
                                                                                 that their hyperexpression promotes cell migration 21, with
investigated in routine clinical practice. In studies where                      the presence of both being related to reduced survival 22. It
only PNI was evaluated, it has a higher incidence than in                        also contributes to worse prognosis as PNI is more preva-
studies looking for multiple risk factors 11.                                    lent in advanced tumours, which in itself is already a nega-
As for clinical diagnosis, between 30 and 40% of patients                        tive prognostic factor.
are symptomatic, and 20% present neurological symptoms                           There are studies that associate PNI with increased risk
when, histologically, the tumour invades the nerve and in-                       of recurrence and reduced survival 15, while others fail to
terferes with its blood supply, causing local oedema, demy-                      detect such a relationship 23. This discrepancy probably
elination and segmental infarction 15. In addition, diagnosis                    results from the way in which the studies are conducted
by imaging (MRI) is only performed when PNI occurs in                            (studies that focus only on detecting PNI, without evaluat-



                                                                                                                                                          21
D.M.V.O. Quintana et al.




Figure 6. Meta-analysis of locoregional recurrence using a random effect model.


                                                                                  metastases 25; therefore, its presence guides a more aggres-
                                                                                  sive approach. In the absence of lymph node metastasis,
                                                                                  PNI leads to greater locoregional recurrence and reduced
                                                                                  disease-free survival, as an independent risk factor, despite
                                                                                  studies with contradictory conclusions. The divergence in
                                                                                  the conclusions of these studies is not due to low sampling,
                                                                                  but rather to methodological differences in the studies,
                                                                                  ranging from the definition of PNI to its measurement.
                                                                                  Considering that PNI has a negative impact on prognosis of
                                                                                  patients with oral SCC, both in relation to overall survival
                                                                                  and to disease-free survival, and is also a negative factor for
                                                                                  locoregional recurrence, we have a perspective that should
                                                                                  be regularly documented in all specimens (with description
                                                                                  of both their presence and absence). This histopathological
Figure 7. Funnel plot of the meta-analysis of locoregional recurrence, with       information must be performed in a standardised way, be-
publication bias.                                                                 ing reported the diameter of the affected nerve, as well as
                                                                                  the presence of a single or multiple invasion focus.
ing other factors such as tumour margin or extension, are                         Regarding the implications for clinical practice, characteri-
more positive) 24.                                                                sation of PNI is important for the development of personal-
High analytical heterogeneity of the studies was identi-                          ised treatment strategies, and should be actively sought by
fied, as well as publication bias. When conducting random                         the pathologist in the evaluation of oral cancer. However,
evaluations of the sample, we observed that PNI represents                        including PNI in TNM staging system is not possible at
a risk factor for lower overall survival, higher mortality,                       present, due to the difficulty of standardising its identifi-
lower disease-free survival and greater risk of locoregional                      cation by anatomopathological analyses. Machine learning
recurrence.                                                                       methods in pathology may improve its detection on the fu-
PNI should be considered a marker that indicates a more                           ture, as digital image analysis and the application of artifi-
aggressive tumour behaviour, with a higher rate of cervical                       cial intelligence develop furthers. The potential of artificial



22
                                                                                   Prognostic impact of perineural invasion in oral cancer: a systematic review




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Acknowledgements                                                                     cers. Kulak Burun Bogaz Ihtis Derg 2008;18:221-226.
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Conflict of interest statement                                                       org/10.1002/cncr.24396
The authors declare no conflict of interest.                                   11
                                                                                     Fagan JJ, Collins B, Barnes L, et al. Perineural invasion in squamous
                                                                                     cell carcinoma of the head and neck. Arch Otolaryngol Head Neck
Funding                                                                              Surg 1998;124:637-640. https://doi.org/10.1001/archotol.124.6.637
This research did not receive any specific grant from fund-
                                                                               12
                                                                                     Schmitd LB, Scanion CS, D’Silva NJ. Perineural invasion in
                                                                                     head and neck cancer. J Dental Res 2018;97:742-750. https://doi.
ing agencies in the public, commercial, or not-for-profit                            org/10.1177/0022034518756297
sectors.                                                                       13
                                                                                     Mesolella M, Iorio B, Misso G, et al. Role of perineural invasion as a
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Authors’ contributions                                                               https://doi.org/10.3892/ol.2016.4265
DMVOQ: design of the work, data collection, data analysis                      14
                                                                                     Chirilă M, Bolboacă SD, Cosgarea M, et al. Perineural invasion of the
                                                                                     major and minor nerves in laryngeal and hypopharyngeal cancer. Oto-
and interpretation; drafting the article. RAD: design of the                         laryngol Head Neck Surg 2009;140:65-69. https://doi.org/10.1016/j.
work; data analysis and interpretation; critical revision of                         otohns.2008.10.019
the article. LPK: final approval of the version to be pub-                     15
                                                                                     Yilmaz T, Hosal AS, Gedikoğlu G, et al. Prognostic significance of vas-
lished.                                                                              cular and perineural invasion in cancer of the larynx. Am J Otolaryn-
                                                                                     gol 1998;19:83-88. https://doi.org/10.1016/s0196-0709(98)90100-4
Ethical consideration                                                          16
                                                                                     Shen WR, Wang YP, Chang JY, et al. Perineural invasion and expres-
                                                                                     sion of nerve growth factor can predict the progression and prog-
This study was approved by the Institutional Ethics Com-                             nosis of oral tongue squamous cell carcinoma. J Oral Pathol Med
mittee of Faculdade de Medicina da Universidade de São                               2014;43:258-264. https://doi.org/10.1111/jop.12133
Paulo (approval number/protocol number 367/17).                                17
                                                                                     Chi AC, Katabi N, Chen HS, et al. Interobserver variation among pa-
The research was conducted ethically, with all study pro-                            thologists in evaluating perineural invasion for oral squamous cell car-
cedures being performed in accordance with the require-                              cinoma. Head Neck Pathol 2016;10:451-464. https://doi.org/10.1007/
                                                                                     s12105-016-0722-9
ments of the World Medical Association’s Declaration of                        18
                                                                                     Leemans CR, Snijders PJF, Brakenhoff RH. The molecular landscape
Helsinki.                                                                            of head and neck cancer. Nat Rev Cancer 2018;18:269-282. https://
Written informed consent was obtained from each partici-                             doi.org/10.1038/nrc.2018.11
pant/patient for study participation and data publication.                     19
                                                                                     Yousem DM, Gad K, Tufano RP. Resectability issues with head and
                                                                                     neck cancer. AJNR Am J Neuroradiol 2006;27:2024-2036.
                                                                               20
                                                                                     Roh J, Muelleman T, Tawfik O, et al. Perineural growh in head and
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