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Abstract

Objectives: Perineural invasion (PNI) was quantitatively analyzed in oral squamous cell carcinoma (OSCC) specimens obtained by radical surgery to correlate with survival outcomes. Methods: This is a retrospective study that reviewed the Cancer registry data between 2009 and 2015. Inclusion criteria were oral cavity cancer, treatment by radical surgery, presence of PNI, and available pathologic samples for S100 staining. Patients with M1 disease and those with synchronous or metachronous cancer during staging work-up were excluded. All pathologic samples were reviewed to confirm PNI status and processed by immunohistochemical staining for S100 to quantify PNI. Pathologic information and staging results were also reviewed, and clinical outcomes were analyzed. Results: The retrospective study included 92 patients; 63 had intratumoral PNI (IPNI) and 29 had extratumoral PNI (EPNI). The average number of PNI foci (APNI) was higher in the EPNI group than in the IPNI group (6.7 vs 3.8, t-test 2-tail significance = 0.021). The 3-year overall survival (OS) and time-to-recurrence (TTR) rates of all patients were 82.5% and 81.2%, respectively. Univariate analysis showed that pathological T4 or N2-3 stage correlated with poor OS, whereas APNI ≥4 correlated with poor TTR. In multivariate analysis, only the pathological N2-3 stage was significantly correlated with poor OS, whereas only APNI ≥ 4 was an independent factor of poor TTR. The 3-year TTR rates were 92.4% and 65.6% for diseases with APNI < 4 and ≥ 4, respectively (P = .008). Conclusions: In patients with OSCC with PNI, a greater amount of PNI identified by S100 staining indicated a poorer TTR regardless of stage and other prognostic factors. Quantification of PNI by S100 immunohistochemistry is a potential method for prognosis prediction.

Keywords

head and neck neoplasms oral cavity cancer perineural invasion immunohistochemistry

Introduction

Oral squamous cell carcinoma (OSCC) is one of the leading causes of cancer-related mortality in Taiwan and in the world.¹ Oral cavity cancer is treated with a combination of different modalities. Advances in multidisciplinary approaches have significantly improved the treatment outcomes and resulted in the development of tailored therapeutic strategies. For example, adjuvant radiotherapy (RT) reduces the risk of tumor recurrence in patients with advanced features.^2,3 Concurrent chemoradiotherapy (CCRT) after radical surgery significantly improves the treatment outcome of patients with a higher risk of recurrence.^4,5 However, changes in adjuvant treatment over time and other controversies need to be further explored.

Several clinicopathological risk factors have been identified and incorporated into staging or risk classification systems.^6,7 Perineural invasion (PNI) is a form of tumor spread that can be broadly defined as tumor cell invasion within the nerve or enclosing the nerve. PNI is mediated by neural cell adhesion molecules that are expressed on the surface of tumor cells.^8–10 The incidence of PNI in OSCC ranges from 12% to 50%. PNI is a risk factor for locoregional recurrence and poor survival outcomes, and the presence of PNI is an indication of postoperative RT or CCRT.¹¹ Different PNI patterns are associated with different prognoses. The eighth edition of the American Joint Committee on Cancer (AJCC) Staging Manual proposed a subdivision of PNI into extratumoral and intratumoral PNI (EPNI and IPNI, respectively).¹² EPNI and IPNI affect prognosis, suggesting that the extent of PNI correlates with prognosis. Therefore, quantitative or subjective measurements may provide valuable information for outcome prediction.

The conventional method for identifying PNI, which is standard hematoxylin and eosin (H&E) staining, relies on the experience of the pathologist and the staining performance. A more objective and sensitive method should be used to improve the detection of PNI. S100 is a nerve system-specific cytoplasmic protein. Staining for S100 by immunohistochemistry (IHC) can identify various nerves and is a sensitive method for the detection of PNI. Kurtz et al¹³ demonstrated that replacing standard H&E staining with S100 or using the 2 in combination increases the detection rate of PNI from 30% to 82% of oral cavity squamous cell carcinoma, and S100 staining improves the PNI detection rate in other cancers. For example, Conte et al¹⁴ reported that failure to detect PNI by H&E can be overcome by S100 staining for colorectal cancer, thereby improving prognosis prediction. In this retrospective study, we performed a quantitative measurement of PNI using S100 IHC staining and evaluated its prognostic effect.

Materials and Methods

Ethical approval was granted by the institutional review board of an associated medical foundation (201800407B0, 2018/March/22, Taoyuan, Taiwan). The need for informed consent was waived owing to the retrospective nature of the study. The reporting of this retrospective study conforms to STROBE guidelines.¹⁵ Clinical records of patients with OSCC who underwent curative treatment in the same hospital between July 2009 and November 2015 were reviewed. All records were retrieved following inclusion and exclusion criteria and de-identified and the identity of any person could not be ascertained in any way. The inclusion criteria were as follows: pathologically diagnosed OSCC, treated by radical surgery with or without adjuvant therapies, and the presence of PNI in pathologic samples. Patients with a previous cancer history, synchronous double cancers, evidence of metastatic disease, and those lacking clinical records were excluded. All pathological samples of selected patients were reviewed to confirm the presence and pattern of PNI. After confirmation, immunostaining for the S100 protein was performed, which indicated the presence of PNI (EPNI or IPNI, Figure 1). Immunostaining was performed using a sensitive avidin-biotin immunoperoxidase technique with the antibodies to the following antigen: S-100 protein (1:500, Leica, NCL-L-S100p). All PNI foci were recorded by one head and neck pathologist. The number of PNI foci in each slide and the average PNI (APNI) per slide were recorded. The methods of this study are reproducible since there are no special procedures to obtain data or materials.

Figure 1.

Immunohistochemistry staining of S100 was performed using a sensitive avidin-biotin immunoperoxidase technique with the antibodies to the following antigen: S100 protein (1:500, Leica, NCL-L-S100p). (a) One intratumoral perineural invasion and (b) 2 extratumoral perineural invasion foci can be identified with assistance of S100 staining.

All patients underwent an extensive presurgical evaluation and complete staging work-up, including computed tomography (CT) or magnetic resonance imaging (MRI) and fluorine-18-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) scan. Radical surgery included tumor excision with ≥1 cm safety margins and neck dissection. Patients with the clinical node-negative disease received neck dissection at levels I to III. Neck dissection at levels I to V was performed in patients with the clinical node-positive disease. Staging results were recorded according to the eighth edition of AJCC Cancer Staging.¹⁶ In cases with pathological risk factors, postoperative RT (60-66 Gy) was guided by the presence of pathological risk factors, such as pathological T4 criteria, node-positive disease, close resection margin, tumor invasion depth ≥10 mm, nerve or vessel invasion, and poorly differentiated histology. The target volume comprised the tumor bed area, regional neck lymphatics, and the possible nerve route from the skull base to the primary tumor. RT was delivered using intensity-modulated RT or volumetric-modulated arc therapy. Concurrent chemotherapy was offered to patients with major risk factors, such as nodal stage 2 or 3 (extranodal extension or multiple node metastases) and positive resection margins. Patients with 3 or more of the above-mentioned minor risk factors also received concurrent chemotherapy during RT. The regimen of concurrent chemotherapy was cisplatin, administered biweekly (50 mg/m²) or triweekly (100 mg/m²), with/without an additional oral 5-fluorouracil prodrug.^17,18

After treatment, follow-up appointments were scheduled at least every 3 months and included physical examinations. Scope examination was optional for patients with moderate to severe trismus, or whenever pharyngeal examination was indicated. If the patient missed their appointment, a follow-up call was made. Another appointment was arranged or the patient's condition was noted if they had passed away or refused follow-up. Imaging studies (CT/MRI) were performed 3 months after completion of CCRT and every 6 to 12 months thereafter. Panendoscopy has performed annually. Outcomes included locoregional recurrence, distant metastasis, and death. Recurrence was confirmed by pathological examination or serial clinical/imaging findings if no tissue was available. The choice of salvage or palliative treatment was based on recurrent disease status and patient preference. Each death was reviewed in detail. Death is unrelated to recurrence or complications was not regarded as treatment failure. Time-to-event and survival were calculated from the date of diagnosis to the date of the corresponding event. For time-to-recurrence, the event was any recurrence, while for overall survival, the event was death. The endpoints were time-to-recurrence (TTR) and overall survival (OS).

Statistical Analyses

The t-test is used to compare the means of the 2 groups. The Kaplan–Meier method was used for survival analysis and the log-rank test was used to determine significance. Multivariate analysis was performed using a Cox regression model. Correlations between each variable and the endpoints were evaluated by univariate and multivariate analyses. Statistical analyses were performed using PASW statistics, version 18 (SPSS Inc., Chicago, IL, USA). P < .05 was considered statistically significant.

Results

Ninety-two patients were included in this study. The median age was 50.5 years old (range: 29-85). The mobile tongue was the most common subsite (66, 59.8%). All patients had PNI. Sixty-three patients (68.5%) had IPNI and 29 (31.5) patients had EPNI. In each slide, the APNI identified by S100 staining ranged from 0.25 to 33 (median: 2.8). Patients with EPNI had an APNI of 6.7, which was significantly higher than that in patients with IPNI (APNI, 3.8; P = .021, 2-tailed t-test). The patient characteristics are listed in Table 1.

Table 1.

Characteristics of All Patients.

Characteristic	Frequency (%)
Age	Median: 50.5 (29-85)
Sex
Male	85 (92.4%)
Female	7 (7.6%)
Smoking
Yes	73 (79.3%)
No	19 (20.7%)
Alcohol
Yes	69 (75%)
No	23 (25%)
Betel quid
Yes	67 (72.8%)
No	25 (27.2%)
Site
Tongue	66 (59.8%)
Mouth floor	3 (3.3%)
Lip	3 (3.3%)
Buccal mucosa	23 (25%)
Gum	2 (2.2%)
Retromolar trigone	6 (6.5%)
Differentiation
Well or moderate	77 (83.7%)
Poor	15 (16.3%)
Pathologic T stage
T1	7 (7.6%)
T2	59 (64.1%)
T3	13 (14.1%)
T4	13 (14.1%)
Pathological N stage
0	48 (52.2%)
1	15 (16.3%)
2b	10 (26.1%)
3b	19 (20.7%)
Perineural invasion
Intratumoral	63 (68.5%)
Extratumoral	29 (31.5%)
Average PNI
4 or more	37 (40.2%)
< 4	55 (59.8%)
Margin distance
< 5 mm	14 (15.2%)
≧5 mm	78 (84.8%)
Vascular invasion
Yes	6 (6.5%)
No	86 (6.5%)
Lymphatic invasion
Yes	4 (4.3%)
No	88 (95.7%)

Abbreviation: PNI, perineural invasion.

The median follow-up was 59.5 months (range: 3-105 months). At the time of analysis, 71 patients were alive. Of the 21 patients who died, 12 died from cancer and the rest died from comorbidities or a second primary cancer. The 3-year OS rate was 82.5%. Pathological T4 stage and pathological N2-3 stage correlated with OS in the univariate analysis (P < .05). OS rates according to different characteristics are listed in Table 2. Pathological N2-3 stage was the only independent prognostic factor in the multivariate analysis (P < .05, Table 3).

Table 2.

Outcome by Patient Characteristic and Treatment Parameter.

Characteristic	3-Year overall survival	P-value	3-Year time-to-recurrence rate	P-value
Sex
Male	82.3%	.573	80.8%	.528
Female	85.7%		85.7%
Smoking
Yes	78.9%	.958	81.8%	.714
No	83.5%		78.9%
Alcohol
Yes	81.1%	.253	80.7%	.748
No	87%		82.6%
Betel quid
Yes	87.6%	.668	80.2%	.549
No	80.6%		83.8%
Differentiation
Poor	80%	.848	80%	.734
Well or Moderate	83.1%		81.5%
Pathological T stage
pT4	61.5%	.011	69.2%	.071
pT1-3	86%		83%
Pathological N stage
N2-3	65.4%	.002	68.5%	.139
N0-1	90.9%		86.2%
Surgical margin
< 5 mm	71.4%	.196	70.7%	.291
≧5 mm	85.9%		83.1%
Perineural invasion
Extratumoral	82.6%	.241	75.2%	.11
Intratumoral	82.5%		84%
Average PNI
4 or more	73.7%	.059	65.6%	.008
< 4	88.8%		92.4%
Vascular invasion
Yes	83.3%	.726	83.3%	.653
No	82.5%		81.1%
Lymphatic invasion
Yes	50%	.127	50%	.108
No	84%		82.6%
Radiotherapy
Yes	79.9%	.242	81%	.681
No	94.1%		82.4%
Chemotherapy
Yes	75%	.24	74.6%	.177
No	86.8%		89.9%

Abbreviation: PNI, perineural invasion.

Table 3.

Multivariate Analysis of Risk Factors for 3-Year Overall Survival and Disease-Free Survival.

Risk factors (n)	3-Year overall survival		3-Year time-to-recurrence rate
Risk factors (n)	HR (95% CI)	P-value	HR (95% CI)	P-value
Pathological T stage		.011		.091
pT4	1.053 (1.012-1.096)		2.491 (0.864-7.182)
pT1-3
Pathological N stage		.006		.318
N2-3	3.838 (1.484-9.928)		1.671 (0.61-4.579)
N0-1
Average PNI		.111		.028
4 or more	2.107 (0.843-5.266)		3.222 (1.132-9.176)
< 4

Abbreviation: PNI, perineural invasion.

The 3-year TTR rate was 81.2%. Tumor recurrence was observed in 22 patients. Nodal recurrence was the most common type of recurrence (n = 17), followed by local recurrence (n = 10) and distant metastasis (n = 9). APNI ≥4 was the only prognostic factor significantly correlated with TTR in univariate (Table 2) and multivariate analyses (P < .05, Table 3). The 3-year TTR rates were 92.4% and 65.6% for diseases with APNI < 4 and ≥ 4, respectively, (P = .008, Figure 2) TTR.

Figure 2.

Kaplan–Meier curves of time-to-recurrence according to average perineural focus per slide.

Discussion

In the present study, we showed that quantification of PNI by S100 IHC staining could be a useful prognostic factor for OSCC with PNI. A higher APNI per slide correlated with poorer TTR, and PNI ≥ 4 per slide was identified as the cut-off point.

Studies have shown different correlations between PNI and prognosis.^19,20 The presence of PNI is a crude description of disease status. Considerable differences in the methodology of data collection and risk factor identification may have led to inconsistent study results.^21,22 The lack of detailed PNI assessment may further confound the results of analyses. To clarify the pattern of PNI, Miller et al¹² proposed a classification according to the extent of PNI. The extent of PNI can be assessed by measuring the distance from each focus of invasion to the tumor edge. The results demonstrated that disease-free survival was longer in patients with IPNI than in those with EPNI. The eighth edition of the AJCC Staging Manual proposed dividing PNI into 2 groups, namely, IPNI and EPNI.^23,24

PNI quantification can provide a detailed assessment of PNI. The amount of PNI correlates with survival outcomes in many malignancies. Wu et al²⁵ reported that the identification of more than 3 PNI foci after radical prostatectomy for prostate cancer is associated with a higher rate of biochemical recurrence. In oral cavity cancer, Wei et al²⁶ demonstrated that the number of PNI foci is a novel parameter for PNI quantification in early OSCC. A higher number of PNI foci identified in pathologic samples are associated with decreased disease-specific survival. Aivazian et al²⁷ showed that multifocal PNI is associated with a worse prognosis irrespective of postoperative RT. These studies support that quantification of PNI extent to predict prognosis is feasible.

To precisely measure the amount of PNI, sensitive methods for the detection of nerves in and around the tumor are necessary. IHC staining for S100, a nervous system-specific cytoplasmic protein, can detect the location of nerves, which provides a sensitive method of PNI identification. Conte et al¹⁴ showed that S100 staining could detect PNI that was undetected by H&E staining in colorectal cancer. In 151 patients, the incidence of PNI increased from 30.5% to 40.4%. Berlingeri-Ramos et al²⁸ also demonstrated that S100 staining improves the detection rate of PNI, especially for small nerves. These studies support the use of S100 IHC staining to increase the PNI detection rate.

Several mechanisms underlying PNI were recently proposed. Some head and neck cancers secrete neurotrophic factors, which can cause interactions between cancer cells and Schwann cells or neurons, such as de-differentiation and cancer cell recruiting.^29,30 Cell migration, changes in motility, and mesenchymal transition also affect PNI in different malignancies.^31,32 Amit et al³³ reported an association between the reprogramming of neurons and cancer growth in head and neck cancer. These pathophysiological theories may provide new treatment strategies to reduce the risk of recurrence. In this study, we did not identify a specific recurrence pattern correlated with PNI that would provide information regarding the molecular basis of PNI. A better understanding of the molecular mechanism underlying the development of PNI in OSCC may help clarify its prognostic effects and lead to the development of more effective therapeutic strategies in the future.^34,35

While quantifying perineural invasion shows its prognostic effect on tumor control, some well-known tumor characteristics, such as T and N stages, may not be identified as independent prognostic factors. This current study selected patients with oral cavity cancer with perineural invasion who were treated using various modalities. Adjuvant treatment was performed for patients with a higher risk of recurrence. It is possible that adjuvant therapy improves treatment outcomes and offsets the negative prognostic effects of pathological T and N stages, as they are indications for adjuvant therapy. Lin et al⁷ demonstrated that treatment outcomes could be similar with proper treatment arranged, except for cancers with extranodal extension or positive resection margins. On the other hand, new prognostic factors can still be discovered under current treatment guidelines. Schmitd et al³⁶ demonstrated new insights into the tumor–nerve relationship and its correlation with treatment outcomes under the current standard of care for oral cancer. In that study, tumor stage did not correlate with treatment outcomes either. Therefore, it is reasonable to conclude that some prognostic factors do not correlate with inferior treatment outcomes under properly designed treatment. Meanwhile, other factors can still be discovered.

The present study had several limitations including its retrospective design and the sole inclusion of patients living in a betel quid chewing endemic area. External validation is necessary to verify the clinical significance of PNI quantification. Furthermore, a prospective observational study or clinical trial should be performed to provide more reliable information.

Conclusions

In patients with OSCC with PNI, a greater extent of PNI identified by S100 staining indicated poorer TTR regardless of stage and other prognostic factors. Quantification of PNI by S100 IHC may be used for prognosis prediction. Prospective studies are warranted to verify the prognostic effect of PNI quantification, which may lead to improved treatment outcomes.

Footnotes

Acknowledgments

The authors would like to acknowledge the cancer center and cancer registry group of Chang Gung Memorial Hospital for their support of data retrieving.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethical Approval

Ethical approval was granted by the institutional review board of an associated medical foundation (201800407B0, 2018/March/22, Taoyuan, Taiwan).

Funding

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: This work was supported by grants CMRPG 3I0011 from the Chang Gung Memorial Hospital in Taiwan.

Human and Animal Rights

This retrospective study was a part of the clinical study approved by institutional review board No. 201800407B0 from Chang Gung Medical Foundation Institutional Review Board.

ORCID iDs

Chia-Hsun Hsieh

Kang-Hsing Fan MD

Abbreviations

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Quantitative Measurement of Perineural Invasion for Prognosis Analysis of Oral Cavity Cancer Treated by Radical Surgery With or Without Adjuvant Therapy

Abstract

Keywords

Introduction

Materials and Methods

Statistical Analyses

Results

Discussion

Conclusions

Footnotes

Acknowledgments

Declaration of Conflicting Interests

Ethical Approval

Funding

Human and Animal Rights

ORCID iDs

Abbreviations

References