Accepted Manuscript Impact of perineural invasion as independent prognostic factor for local and regional failure in oral squamous cell carcinoma Achille Tarsitano, Maria Lucia Tardio, Claudio Marchetti PII:
S2212-4403(14)01311-X
DOI:
10.1016/j.oooo.2014.10.004
Reference:
OOOO 1041
To appear in:
Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Received Date: 4 August 2014 Revised Date:
26 September 2014
Accepted Date: 7 October 2014
Please cite this article as: Tarsitano A, Tardio ML, Marchetti C, Impact of perineural invasion as independent prognostic factor for local and regional failure in oral squamous cell carcinoma, Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology (2014), doi: 10.1016/j.oooo.2014.10.004. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Impact of perineural invasion as independent prognostic factor for
Achille Tarsitano1, Maria Lucia Tardio2, Claudio Marchetti3. 1
RI PT
local and regional failure in oral squamous cell carcinoma.
Researcher at Department of Biomedical and Neuromotorial Science, University of
Bologna. Maxillofacial Surgery Unit, Policlinico S.Orsola-Malpighi.
Medical Doctor, Section of Pathology, S. Orsola-Malpighi Hospital, Bologna, Italy.
3
Professor of Maxillofacial Surgery at Department of Biomedical and Neuromotorial
SC
2
Malpighi.
Corresponding Author: Achille Tarsitano MD
TE D
Maxillofacial Surgery Unit
M AN U
Science, University of Bologna. Maxillofacial Surgery Unit, Policlinico S.Orsola-
Alma Mater Studiorum University of Bologna Policlinico S. Orsola-Malpighi
EP
via Massarenti, 9 40100 Bologna, Italy email: [email protected]
AC C
[email protected] fax: +390516364160
Keywords : Oral squamous cell carcinoma; perineural invasion; prognosis; neural spread.
ACCEPTED MANUSCRIPT
No funding sources supported this study. We disclose any prior presentation of abstracts at meetings and posting any part or all of
RI PT
the content.
Abstract word count: 116
SC
Manuscript word count: 2.355 Number of references: 26
M AN U
Number of figures: 6
AC C
EP
TE D
Number of tables: 5
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
Abstract
Objective: Perineural invasion (PNI) is frequent in oral squamous cell carcinoma
TE D
(OSCC) and could play an important role in treatment decisions.
Study Design: This retrospective study used multivariate analysis to evaluate the impact of PNI on locoregional recurrence, neck metastases, and survival in 236 consecutive
EP
patients with oral cancer.
Results: There were significant differences in the local (p = 0.007) and regional (p =
AC C
0.041) failure rates in the PNI+ group compared to the PNI- group. Univariate analysis demonstrated that PNI+ patients had significantly worse locoregional control (p = 0.011), disease-specific survival (p = 0.023), and overall survival (p = 0.046) than PNIpatients.
Conclusion: PNI was an independent predictor of local and regional failure in a welldefined
homogeneous
OSCC
population.
ACCEPTED MANUSCRIPT
Introduction Although advances in the multimodal treatment of oral squamous cell carcinoma
RI PT
(OSCC) have improved outcomes, prognoses for patients with oral cancer remain poor, with locoregional recurrence being the primary cause of treatment failure.1,2
To assess risk factors for disease outcome in OSCC adequately, many clinical factors and histopathological features must be analyzed to help identify patients at high
SC
risk for recurrence.3
M AN U
Perineural invasion (PNI) is one of these important markers. PNI is a form of metastatic tumor that spreads to the nerve bundles in the surrounding tissues, but unlike vascular or lymphatic invasion, it hinders the ability to establish local control of a malignancy because neoplastic cells can travel far from the primary lesion along nerve tracts and are often missed during surgery. As a result, these tumors can cause pain and
TE D
persistent growth with a long clinical course and late onset of metastases, a pattern that has been observed in neurotropic tumor types such as melanoma, prostate, and pancreatic cancer, and adenoid cystic carcinoma of the salivary glands.
EP
In OSCC, histological evidence of PNI or “neurotropic carcinomatous spread” is a poor prognostic factor and may indicate the need for adjuvant therapy.4
AC C
The occurrence of PNI in squamous cell carcinomas of the head and neck region is quite high, ranging from 6% to 30%, and it could play an important role in treatment decisions.5
Although the National Comprehensive Cancer Network (NCCN)6 for oral cancer
states that the presence of PNI is an indicator for adjuvant radiotherapy in early-stage patients and the European Organization for Research and Treatment of Cancer (EORTC) includes PNI among the criteria defining high-risk patients, in trial #22931,
ACCEPTED MANUSCRIPT
such patients did not benefit from adjuvant chemoradiotherapy.7 The proper management of PNI-positive patients remains controversial due to a lack of solid
RI PT
scientific evidence.8 This study focuses on the role of PNI in oral cancer, using multivariate analysis
SC
to examine the impact of PNI on locoregional recurrence, neck metastases, and survival.
Patients and Methods
M AN U
This retrospective study included 236 consecutive patients with a histological diagnosis of primary OSCC seen at the Maxillofacial Surgery Unit of the University of Bologna between 2006 and 2013. Institutional review board approval was not required. The data analyzed included patient age, sex, alcohol and tobacco use, tumor location, TNM stage, treatment modalities, resection margins, grade of differentiation,
TE D
PNI, lymph node involvement, extracapsular spread (ECS), locoregional control (LRC), and survival. In all cases, local and cervical computed tomography (CT) or magnetic resonance imaging (MRI) was performed for radiological locoregional preoperative
EP
staging.
The inclusion criteria were (1) previously untreated OSCC and (2) patients
AC C
managed with surgery. The mean follow-up was 52.4 (range 16–88) months and was considered to be sufficient for detecting local or regional recurrence.
Treatment Modality
Patient treatment consisted of composite resection, including excision of the primary tumor with ipsilateral or bilateral neck dissection. Table 1 details the surgical approach and reconstruction types according to PNI status. Selective supraomohyoid neck
ACCEPTED MANUSCRIPT
dissection was performed simultaneously with tumor resection in all cases diagnosed as cN0. Radical or modified radical neck dissection was performed for stage cN+ patients.
RI PT
Adjuvant therapy was administered according to the National Comprehensive Cancer Network guidelines.8
Histopathological analysis
SC
Each specimen was examined for PNI, lymphatic-vascular infiltration, tumor differentiation, and surgical margins. For each patient, slides of the surgical specimen
M AN U
stained with hematoxylin and eosin were subjected to a thorough histopathological examination to document all foci of PNI by a pathologist who was blinded to the clinical outcomes. The nerves were immunostained when the histological features were in doubt.
TE D
PNI was considered positive when tumor cells were identified in any of the three layers of the nerve sheath or a tumor was identified in close proximity to a nerve, involving more than one third of its circumference, as proposed by Liebig et al.9 (Figure
EP
1).
The extent of PNI was categorized according to the classification of Chinn et
AC C
al.10 as focal (1 focus of PNI), moderate (2–5 foci of PNI), or extensive (>5 foci of PNI). The size of the invaded nerve was categorized as small (nerve 1 mm).
For each focus of PNI identified, the distance to the tumor edge (in mm) was
measured, with the tumor edge permitting us to define the PNI as intra-, peri-, and extra-tumoral, according to the definition of Miller et al.11 Hence, when PNI was identified into the tumor it was defined as intra-tumoral; when PNI was identified
ACCEPTED MANUSCRIPT
between 0 and 2 mm by tumor-host interface it was peri-tumoral; if PNI was identified at a distance by tumor front of invasion bigger than 2 mm it was defined extratumoral
RI PT
(Figures 2-3-4).
Statistical analysis
SC
The outcomes of interest were overall survival (OS), disease-specific survival (DSS),
and LRC. OS was defined as the time from diagnosis of the first primary to death by
M AN U
any cause; DSS was defined as the time from diagnosis of the first primary to death from OSCC, where the occurrence of a second primary was treated as a censored event; LRC was defined as time from treatment to local or regional recurrence. The Kaplan–Meier method and log-rank test were used to test for differences in the survival functions between strata defined by clinical variables. Univariate and
TE D
multivariate models were used to explore the associations of clinical variables with time-to-event outcomes. Multivariate analysis was performed for OS, DSS, and LRC. All statistical analyses were done using SPSS ver. 13. A two-tailed P-value of
AC C
Results
EP
0.05 or less was considered statistically significant.
The demographics of the cohort are summarized in Table 2. Ablative surgery was the main treatment performed in all patients and surgical defects were closed or reconstructed using local or free flaps (Table 1). Elective neck dissection of levels I–III was performed in 116 patients (49.1%), modified radical neck dissection was performed in 48 patients (20.4%), and 72 (30.5%) patients did not undergo neck dissection. Of the patients, 156 (66.1%) were treated with surgery alone, while 80 (33.9%) received
ACCEPTED MANUSCRIPT
postoperative adjuvant radiotherapy with a radiation dose of 50–70 Gy. Tumors of the tongue and floor of the mouth appeared to be more frequently PNI-positive (PNI+)
RI PT
compared to other sites of the oral cavity (Table 2). The overall failure rate was 30% (71/236). There was a significant difference in
the local failure rate between the PNI+ group (60.7%, 31/51) and the PNI-negative
SC
(PNI–) group (11.9%, 22/185; p = 0.007). There was also a significant difference in the
regional failure rate (PNI+: 19.6%, 10/51; PNI−: 3.8%, 7/185; p = 0.041). No
M AN U
significant difference was found in the distant failure rate (1.9%, 1/51 vs. 0%, 0/185; p = 1.0).
Univariate analysis demonstrated that PNI+ patients had significantly worse LRC (p = 0.011), DSS (p = 0.023), and OS (p = 0.046) than PNI– patients. The 5-year survival estimates of both groups are shown in Table 3.
TE D
Kaplan–Meier curves show this difference in terms of the disease-free survival (Figure 5) and local failure risk (Figure 6).
The histological descriptors of PNI (focal, moderate, and extensive), type of
EP
nerve involved (small vs. large), and intra-, peri-, and extra-tumoral invasion were also analyzed. Of the PNI+ patients with loco-regional failure, 59% had extensive PNI, 30%
AC C
had focal PNI, and 11% had moderate PNI (Table 4). Extensive nerve involvement, according to the classification of Chinn et al.,12 significantly affected the LRC (p
= 0.048). Small nerves were predominantly involved (69%) compared to large nerves
(31%) and the vast majority (65%) had intra- or peri-tumoral invasion. The invasion of large nerves significantly affected the locoregional failure rate (p = 0.044) compared to small nerves (Table 4). Extra-tumoral PNI was significantly
ACCEPTED MANUSCRIPT
related to the locoregional failure rate compared to intra- or peri-tumoral PNI (p = 0.05) (Table 4).
RI PT
Using univariate and multivariate analyses, PNI was found to be an independent predictor of regional (p = 0.009, OR = 5.590, 95% CI 0.572–271.078) and local (p = 0.032, OR: 5.899, 95% CI 0.568–213.065) recurrence (Table 5). The risk of
SC
developing neck recurrence was higher in PNI+ than in PNI– patients (69.3% vs. 19.6%). Tumor stage (p = 0.87, OR = 1.133, 95% CI 0.161–7.984) and grade (p = 0.51,
M AN U
OR = 1.250, 95% CI 1.028–1.521) did not significantly affect the risk of regional recurrence among PNI+ patients (Table 5). Pattern of invasion types 4 and 5 (according to the classification of Brandwein-Gensler et al.3) did not to alter the risk of locoregional failure (Table 5). Positive surgical margins (p = 0.049) and extra-capsular spread (p = 0.050) were negative predictors of locoregional failure in the multivariate
TE D
analysis (Table 5).
Elective neck dissection of cervical lymph nodal levels I–III significantly reduced the risk of regional recurrence in cN0 patients with PNI+ OSCC (p = 0.046,
AC C
Discussion
EP
OR = 0.025, 95% CI 0.001–0.645, Table 5).
The prognosis of, and therefore treatment decisions for, OSCC are currently based on TNM staging, as determined by clinical examination, imaging tests, and histopathological features observed in a biopsy that are believed to be risk factors affecting patient outcomes.12 Many recent studies have emphasized the importance of PNI as a risk factor affecting patients with head and neck squamous cell cancer. The preponderance of
ACCEPTED MANUSCRIPT
literature evidence demonstrates that PNI is a significant predictor of the presence of occult neck node metastasis.13–16
RI PT
Tai et al.14 reported on 307 patients with oral cancers at various sites, and demonstrated that PNI was an independent predictor of neck metastasis, even in early-
stage tumors, while Miller et al.11 found that PNI also correlated with the number of the
infiltrated cervical nodes. Larsen et al.17 reported that the ability of OSCC to spread to
SC
cervical lymph nodes was significantly related to nerve invasion. Ross et al.16
M AN U
demonstrated that neural invasion was a strong histological predictor of cervical metastasis that should be considered to avoid underestimating neck status. Nevertheless, Wallwork et al.18 detected no significant association between PNI and the presence of lymph node metastases in OSCC of the floor of the mouth. Despite the well-established correlation between PNI and higher treatment
TE D
failure rates in OSCC patients,19,20 there are no definitive findings regarding its independent role in locoregional recurrence, which could guide more efficient, evidence-based management of these patients. In the present study, PNI was an
EP
independent predictor of cervical lymph node recurrence and local recurrence. Other series have reported an increased risk of regional recurrence with PNI.16–19
AC C
In a large series, Tai et al.13,14 demonstrated that PNI was an independent predictor of regional, but not local, failure in OSCC. In a multivariate analysis of 101 OSCC patients, Rahima et al.8 found that PNI was significantly associated with only regional recurrence. D’Cruz et al.21 reported that the incidence of neck recurrence was
significantly higher among PNI+ patients than patients without perineural spread. Huang et al.22 reported that PNI was significantly associated with regional recurrence in a univariate analysis, but not in a multivariate analysis, whereas Wang et al.23 failed to
ACCEPTED MANUSCRIPT
find any significant difference in the incidence of PNI between recurrence and no recurrence groups.
RI PT
The increased risk of regional recurrence in patients with PNI+ tumors is reflected in their poorer survival rates. In a Cox’s multivariate analysis of 210 patients with OSCC, Ling et al.24 found that PNI was an independent predictor of the 5-year OS,
SC
whereas Tai et al.13,14 demonstrated that PNI was an independent predictor of a poor 5year DSS.
M AN U
Less clear is the role of PNI as an independent predictor of local recurrence. Although several studies have reported on a correlation between PNI and local recurrence,23,25,26 the majority failed to demonstrate that PNI was an independent prognostic factor.
To the best of our knowledge, this study is the first in which PNI is identified,
TE D
using univariate and multivariate analysis, as an independent predictor of local and regional failure in a well-defined homogeneous OSCC population. Here, PNI is identified as an independent risk factor for reduced DSS and LRC. This evidence is, in
EP
our opinion, due to the impossibility of obtaining a clear resection margin when PNI is present. Neoplastic cells could be present along the nerves, in the perineural space,
AC C
beyond the surgical margin. Our data might explain the high risk of local relapse even when the pathological surgical margins appear clear. This hypothesis justifies the importance of the correct detection of PNI in the surgical specimen and the role played by adjuvant therapy, even when other risk factors are not identified. Although the presence of PNI has been shown to affect prognosis, few studies have examined how the extent of PNI affects recurrence. Fagan et al.19 reported that PNI involving even small nerves (
S2212-4403(14)01311-X
DOI:
10.1016/j.oooo.2014.10.004
Reference:
OOOO 1041
To appear in:
Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Received Date: 4 August 2014 Revised Date:
26 September 2014
Accepted Date: 7 October 2014
Please cite this article as: Tarsitano A, Tardio ML, Marchetti C, Impact of perineural invasion as independent prognostic factor for local and regional failure in oral squamous cell carcinoma, Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology (2014), doi: 10.1016/j.oooo.2014.10.004. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Impact of perineural invasion as independent prognostic factor for
Achille Tarsitano1, Maria Lucia Tardio2, Claudio Marchetti3. 1
RI PT
local and regional failure in oral squamous cell carcinoma.
Researcher at Department of Biomedical and Neuromotorial Science, University of
Bologna. Maxillofacial Surgery Unit, Policlinico S.Orsola-Malpighi.
Medical Doctor, Section of Pathology, S. Orsola-Malpighi Hospital, Bologna, Italy.
3
Professor of Maxillofacial Surgery at Department of Biomedical and Neuromotorial
SC
2
Malpighi.
Corresponding Author: Achille Tarsitano MD
TE D
Maxillofacial Surgery Unit
M AN U
Science, University of Bologna. Maxillofacial Surgery Unit, Policlinico S.Orsola-
Alma Mater Studiorum University of Bologna Policlinico S. Orsola-Malpighi
EP
via Massarenti, 9 40100 Bologna, Italy email: [email protected]
AC C
[email protected] fax: +390516364160
Keywords : Oral squamous cell carcinoma; perineural invasion; prognosis; neural spread.
ACCEPTED MANUSCRIPT
No funding sources supported this study. We disclose any prior presentation of abstracts at meetings and posting any part or all of
RI PT
the content.
Abstract word count: 116
SC
Manuscript word count: 2.355 Number of references: 26
M AN U
Number of figures: 6
AC C
EP
TE D
Number of tables: 5
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
Abstract
Objective: Perineural invasion (PNI) is frequent in oral squamous cell carcinoma
TE D
(OSCC) and could play an important role in treatment decisions.
Study Design: This retrospective study used multivariate analysis to evaluate the impact of PNI on locoregional recurrence, neck metastases, and survival in 236 consecutive
EP
patients with oral cancer.
Results: There were significant differences in the local (p = 0.007) and regional (p =
AC C
0.041) failure rates in the PNI+ group compared to the PNI- group. Univariate analysis demonstrated that PNI+ patients had significantly worse locoregional control (p = 0.011), disease-specific survival (p = 0.023), and overall survival (p = 0.046) than PNIpatients.
Conclusion: PNI was an independent predictor of local and regional failure in a welldefined
homogeneous
OSCC
population.
ACCEPTED MANUSCRIPT
Introduction Although advances in the multimodal treatment of oral squamous cell carcinoma
RI PT
(OSCC) have improved outcomes, prognoses for patients with oral cancer remain poor, with locoregional recurrence being the primary cause of treatment failure.1,2
To assess risk factors for disease outcome in OSCC adequately, many clinical factors and histopathological features must be analyzed to help identify patients at high
SC
risk for recurrence.3
M AN U
Perineural invasion (PNI) is one of these important markers. PNI is a form of metastatic tumor that spreads to the nerve bundles in the surrounding tissues, but unlike vascular or lymphatic invasion, it hinders the ability to establish local control of a malignancy because neoplastic cells can travel far from the primary lesion along nerve tracts and are often missed during surgery. As a result, these tumors can cause pain and
TE D
persistent growth with a long clinical course and late onset of metastases, a pattern that has been observed in neurotropic tumor types such as melanoma, prostate, and pancreatic cancer, and adenoid cystic carcinoma of the salivary glands.
EP
In OSCC, histological evidence of PNI or “neurotropic carcinomatous spread” is a poor prognostic factor and may indicate the need for adjuvant therapy.4
AC C
The occurrence of PNI in squamous cell carcinomas of the head and neck region is quite high, ranging from 6% to 30%, and it could play an important role in treatment decisions.5
Although the National Comprehensive Cancer Network (NCCN)6 for oral cancer
states that the presence of PNI is an indicator for adjuvant radiotherapy in early-stage patients and the European Organization for Research and Treatment of Cancer (EORTC) includes PNI among the criteria defining high-risk patients, in trial #22931,
ACCEPTED MANUSCRIPT
such patients did not benefit from adjuvant chemoradiotherapy.7 The proper management of PNI-positive patients remains controversial due to a lack of solid
RI PT
scientific evidence.8 This study focuses on the role of PNI in oral cancer, using multivariate analysis
SC
to examine the impact of PNI on locoregional recurrence, neck metastases, and survival.
Patients and Methods
M AN U
This retrospective study included 236 consecutive patients with a histological diagnosis of primary OSCC seen at the Maxillofacial Surgery Unit of the University of Bologna between 2006 and 2013. Institutional review board approval was not required. The data analyzed included patient age, sex, alcohol and tobacco use, tumor location, TNM stage, treatment modalities, resection margins, grade of differentiation,
TE D
PNI, lymph node involvement, extracapsular spread (ECS), locoregional control (LRC), and survival. In all cases, local and cervical computed tomography (CT) or magnetic resonance imaging (MRI) was performed for radiological locoregional preoperative
EP
staging.
The inclusion criteria were (1) previously untreated OSCC and (2) patients
AC C
managed with surgery. The mean follow-up was 52.4 (range 16–88) months and was considered to be sufficient for detecting local or regional recurrence.
Treatment Modality
Patient treatment consisted of composite resection, including excision of the primary tumor with ipsilateral or bilateral neck dissection. Table 1 details the surgical approach and reconstruction types according to PNI status. Selective supraomohyoid neck
ACCEPTED MANUSCRIPT
dissection was performed simultaneously with tumor resection in all cases diagnosed as cN0. Radical or modified radical neck dissection was performed for stage cN+ patients.
RI PT
Adjuvant therapy was administered according to the National Comprehensive Cancer Network guidelines.8
Histopathological analysis
SC
Each specimen was examined for PNI, lymphatic-vascular infiltration, tumor differentiation, and surgical margins. For each patient, slides of the surgical specimen
M AN U
stained with hematoxylin and eosin were subjected to a thorough histopathological examination to document all foci of PNI by a pathologist who was blinded to the clinical outcomes. The nerves were immunostained when the histological features were in doubt.
TE D
PNI was considered positive when tumor cells were identified in any of the three layers of the nerve sheath or a tumor was identified in close proximity to a nerve, involving more than one third of its circumference, as proposed by Liebig et al.9 (Figure
EP
1).
The extent of PNI was categorized according to the classification of Chinn et
AC C
al.10 as focal (1 focus of PNI), moderate (2–5 foci of PNI), or extensive (>5 foci of PNI). The size of the invaded nerve was categorized as small (nerve 1 mm).
For each focus of PNI identified, the distance to the tumor edge (in mm) was
measured, with the tumor edge permitting us to define the PNI as intra-, peri-, and extra-tumoral, according to the definition of Miller et al.11 Hence, when PNI was identified into the tumor it was defined as intra-tumoral; when PNI was identified
ACCEPTED MANUSCRIPT
between 0 and 2 mm by tumor-host interface it was peri-tumoral; if PNI was identified at a distance by tumor front of invasion bigger than 2 mm it was defined extratumoral
RI PT
(Figures 2-3-4).
Statistical analysis
SC
The outcomes of interest were overall survival (OS), disease-specific survival (DSS),
and LRC. OS was defined as the time from diagnosis of the first primary to death by
M AN U
any cause; DSS was defined as the time from diagnosis of the first primary to death from OSCC, where the occurrence of a second primary was treated as a censored event; LRC was defined as time from treatment to local or regional recurrence. The Kaplan–Meier method and log-rank test were used to test for differences in the survival functions between strata defined by clinical variables. Univariate and
TE D
multivariate models were used to explore the associations of clinical variables with time-to-event outcomes. Multivariate analysis was performed for OS, DSS, and LRC. All statistical analyses were done using SPSS ver. 13. A two-tailed P-value of
AC C
Results
EP
0.05 or less was considered statistically significant.
The demographics of the cohort are summarized in Table 2. Ablative surgery was the main treatment performed in all patients and surgical defects were closed or reconstructed using local or free flaps (Table 1). Elective neck dissection of levels I–III was performed in 116 patients (49.1%), modified radical neck dissection was performed in 48 patients (20.4%), and 72 (30.5%) patients did not undergo neck dissection. Of the patients, 156 (66.1%) were treated with surgery alone, while 80 (33.9%) received
ACCEPTED MANUSCRIPT
postoperative adjuvant radiotherapy with a radiation dose of 50–70 Gy. Tumors of the tongue and floor of the mouth appeared to be more frequently PNI-positive (PNI+)
RI PT
compared to other sites of the oral cavity (Table 2). The overall failure rate was 30% (71/236). There was a significant difference in
the local failure rate between the PNI+ group (60.7%, 31/51) and the PNI-negative
SC
(PNI–) group (11.9%, 22/185; p = 0.007). There was also a significant difference in the
regional failure rate (PNI+: 19.6%, 10/51; PNI−: 3.8%, 7/185; p = 0.041). No
M AN U
significant difference was found in the distant failure rate (1.9%, 1/51 vs. 0%, 0/185; p = 1.0).
Univariate analysis demonstrated that PNI+ patients had significantly worse LRC (p = 0.011), DSS (p = 0.023), and OS (p = 0.046) than PNI– patients. The 5-year survival estimates of both groups are shown in Table 3.
TE D
Kaplan–Meier curves show this difference in terms of the disease-free survival (Figure 5) and local failure risk (Figure 6).
The histological descriptors of PNI (focal, moderate, and extensive), type of
EP
nerve involved (small vs. large), and intra-, peri-, and extra-tumoral invasion were also analyzed. Of the PNI+ patients with loco-regional failure, 59% had extensive PNI, 30%
AC C
had focal PNI, and 11% had moderate PNI (Table 4). Extensive nerve involvement, according to the classification of Chinn et al.,12 significantly affected the LRC (p
= 0.048). Small nerves were predominantly involved (69%) compared to large nerves
(31%) and the vast majority (65%) had intra- or peri-tumoral invasion. The invasion of large nerves significantly affected the locoregional failure rate (p = 0.044) compared to small nerves (Table 4). Extra-tumoral PNI was significantly
ACCEPTED MANUSCRIPT
related to the locoregional failure rate compared to intra- or peri-tumoral PNI (p = 0.05) (Table 4).
RI PT
Using univariate and multivariate analyses, PNI was found to be an independent predictor of regional (p = 0.009, OR = 5.590, 95% CI 0.572–271.078) and local (p = 0.032, OR: 5.899, 95% CI 0.568–213.065) recurrence (Table 5). The risk of
SC
developing neck recurrence was higher in PNI+ than in PNI– patients (69.3% vs. 19.6%). Tumor stage (p = 0.87, OR = 1.133, 95% CI 0.161–7.984) and grade (p = 0.51,
M AN U
OR = 1.250, 95% CI 1.028–1.521) did not significantly affect the risk of regional recurrence among PNI+ patients (Table 5). Pattern of invasion types 4 and 5 (according to the classification of Brandwein-Gensler et al.3) did not to alter the risk of locoregional failure (Table 5). Positive surgical margins (p = 0.049) and extra-capsular spread (p = 0.050) were negative predictors of locoregional failure in the multivariate
TE D
analysis (Table 5).
Elective neck dissection of cervical lymph nodal levels I–III significantly reduced the risk of regional recurrence in cN0 patients with PNI+ OSCC (p = 0.046,
AC C
Discussion
EP
OR = 0.025, 95% CI 0.001–0.645, Table 5).
The prognosis of, and therefore treatment decisions for, OSCC are currently based on TNM staging, as determined by clinical examination, imaging tests, and histopathological features observed in a biopsy that are believed to be risk factors affecting patient outcomes.12 Many recent studies have emphasized the importance of PNI as a risk factor affecting patients with head and neck squamous cell cancer. The preponderance of
ACCEPTED MANUSCRIPT
literature evidence demonstrates that PNI is a significant predictor of the presence of occult neck node metastasis.13–16
RI PT
Tai et al.14 reported on 307 patients with oral cancers at various sites, and demonstrated that PNI was an independent predictor of neck metastasis, even in early-
stage tumors, while Miller et al.11 found that PNI also correlated with the number of the
infiltrated cervical nodes. Larsen et al.17 reported that the ability of OSCC to spread to
SC
cervical lymph nodes was significantly related to nerve invasion. Ross et al.16
M AN U
demonstrated that neural invasion was a strong histological predictor of cervical metastasis that should be considered to avoid underestimating neck status. Nevertheless, Wallwork et al.18 detected no significant association between PNI and the presence of lymph node metastases in OSCC of the floor of the mouth. Despite the well-established correlation between PNI and higher treatment
TE D
failure rates in OSCC patients,19,20 there are no definitive findings regarding its independent role in locoregional recurrence, which could guide more efficient, evidence-based management of these patients. In the present study, PNI was an
EP
independent predictor of cervical lymph node recurrence and local recurrence. Other series have reported an increased risk of regional recurrence with PNI.16–19
AC C
In a large series, Tai et al.13,14 demonstrated that PNI was an independent predictor of regional, but not local, failure in OSCC. In a multivariate analysis of 101 OSCC patients, Rahima et al.8 found that PNI was significantly associated with only regional recurrence. D’Cruz et al.21 reported that the incidence of neck recurrence was
significantly higher among PNI+ patients than patients without perineural spread. Huang et al.22 reported that PNI was significantly associated with regional recurrence in a univariate analysis, but not in a multivariate analysis, whereas Wang et al.23 failed to
ACCEPTED MANUSCRIPT
find any significant difference in the incidence of PNI between recurrence and no recurrence groups.
RI PT
The increased risk of regional recurrence in patients with PNI+ tumors is reflected in their poorer survival rates. In a Cox’s multivariate analysis of 210 patients with OSCC, Ling et al.24 found that PNI was an independent predictor of the 5-year OS,
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whereas Tai et al.13,14 demonstrated that PNI was an independent predictor of a poor 5year DSS.
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Less clear is the role of PNI as an independent predictor of local recurrence. Although several studies have reported on a correlation between PNI and local recurrence,23,25,26 the majority failed to demonstrate that PNI was an independent prognostic factor.
To the best of our knowledge, this study is the first in which PNI is identified,
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using univariate and multivariate analysis, as an independent predictor of local and regional failure in a well-defined homogeneous OSCC population. Here, PNI is identified as an independent risk factor for reduced DSS and LRC. This evidence is, in
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our opinion, due to the impossibility of obtaining a clear resection margin when PNI is present. Neoplastic cells could be present along the nerves, in the perineural space,
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beyond the surgical margin. Our data might explain the high risk of local relapse even when the pathological surgical margins appear clear. This hypothesis justifies the importance of the correct detection of PNI in the surgical specimen and the role played by adjuvant therapy, even when other risk factors are not identified. Although the presence of PNI has been shown to affect prognosis, few studies have examined how the extent of PNI affects recurrence. Fagan et al.19 reported that PNI involving even small nerves (
