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ORIGINAL ARTICLE
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Factors predicting the perineural invasion in carcinoma oral cavity


1 Department of Medical Oncology, Acharya Harihar Post Graduate Institute of Cancer, Cuttack, India
2 Department of Radiation Oncology, Acharya Harihar Post Graduate Institute of Cancer, Cuttack, India
3 Department of Oral Medicine and Radiology, Institute of Dental Sciences, Bhubaneshwar, Odisha, India
4 Department of Pathology, Kalinga Institute of Medical Sciences, Bhubaneshwar, Odisha, India

Date of Submission25-Aug-2021
Date of Acceptance29-Aug-2021
Date of Web Publication02-Nov-2021

Correspondence Address:
Avinash Ajitesh,
Sai Karuna, Surya Vihar, Link Road, Cuttack, Odisha
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_1455_21

 > Abstract 


Objective: This study to evaluate clinicopathological parameters such as age, tumor location, tumor size, grade, depth of invasion (DOI), lymphovascular space invasion (LVSI), lymph node metastasis, and stage that predict peri-neural invasion (PNI) in oral squamous cell carcinoma (OSCC).
Material and Methods: A retrospective study on 1716 postoperative OSCC patients who satisfied the eligibility criteria and treated from January 2009 to December 2019 was analyzed using IBM SPSS V23. Mean and percentage were assessed using descriptive statistics. Wilcoxon–Mann–Whitney U-test was used to compare continuous variables, while Chi-square test was used to compare discrete variables between PNI-positive and PNI-negative groups. Two-tailed P < 0.05 was considered to be statistically significant.
Results: Out of 1716 patients, 553 were PNI positive. The mean age was 48.76 ± 12.42 years in PNI-positive patients while 51.52 ± 12.51 years in PNI-negative patients. Males outnumbered females. The most common primary was carcinoma buccal mucosa (204, 36.9%), followed by carcinoma of oral tongue (161,29.1%). Maximum tumor size was 3.14 ± 1.20 cm in PNI-positive patients whereas 2.78 ± 1.22 cm in PNI-negative patients. Sixty (10.84%) patients in PNI-positive group and 51 (4.38%) in PNI-negative group had LVSI positive. Lymph node involvement was observed in 305 (55.13%) patients in PNI-positive group whereas 358 (30.78%) patients in PNI-negative group. Maximum number 228 (41.3%) in PNI-positive patients were in Stage IVA disease.
Conclusion: PNI is one of the important adverse prognostic factors having a definite correlation with anatomical subsite, tumor size, grade, DOI, LVSI, lymph node involvement, and stage of the disease. PNI should be analyzed in postoperative histopathology report of OSCC that guides the clinician for adjuvant therapy.

Keywords: Head-and-neck cancer, histopathology, oral cavity, peri-neural invasion, squamous cell carcinoma



How to cite this URL:
Samanta DR, Surendra S, Suresh K R, Ajitesh A, Maitree P, Tapas K D, Sanat K B, Rabi N M. Factors predicting the perineural invasion in carcinoma oral cavity. J Can Res Ther [Epub ahead of print] [cited 2021 Dec 6]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=329831




 > Introduction Top


Head-and-neck cancer represents 7.6% of all malignancies.[1] Oral squamous cell carcinoma (OSCC) is the most common head-and-neck cancer represents the 8th most common cancer in developing countries.[2],[3] Factors such as resected margins, grade, depth of invasion (DOI), lymphovascular space invasion (LVSI), peri-neural invasion (PNI), and extranodal extension (ENE) predict the therapeutic outcome and are incorporated in the AJCC 8th edition as adverse prognostic factors in OSCC.[4],[5]

Here is a study to evaluate the incidence of positive PNI and to find out its correlation with grade, thickness, LVSI, lymph node involvement, and ENE in OSCC due to its paucity in Indian literature.


 > Materials And Methods Top


Study design

This study was a retrospective cross-sectional study of OSCC undertaken in a tertiary cancer center from January 01, 2009, to December 31, 2019. The data were obtained from the case records of the patients and collected from the medical record section of the hospital and also from a reputed pathological laboratory. The data quality was ensured for completeness and accuracy.

Ethical approval for this study was obtained from the Institutional Ethics Committee.

Data

During the study period, 4237 patients of OSCC were screened for inclusion in this study. Histopathology-proven 2521 OSCC patients who did not meet the eligibility criteria, i.e., age <18 years, received prior neoadjuvant chemotherapy or radiotherapy, and had recurrent disease or metastatic disease at presentation were excluded from the study. Further, 37 OSCC patients whose postoperative histopathology reports were incomplete or did not have reporting on the PNI status of the patients were excluded from the study. The total number of 1716 eligible patients of OSCC was taken for analysis, as shown in [Figure 1].{Figure1}

Two types of patient information were retrospectively collected from the clinical case records that included demographic characteristics such as age and gender and clinicopathological characteristics such as site of tumor, gross appearance of tumor, grade of tumor, maximum tumor size, DOI, LVSI, PNI, number of positive lymph nodes, ENE, and tumor staging.

The personal identification data of patients were not collected.

In this study, we categorized OSCC into two groups based on the presence or absence of the PNI in postoperative histopathology report. Data quality was ensured by a full discussion among the authors.

Statistical analysis

The data were analyzed using International Business Machine Statistical Package for the Social Sciences Statistics, Version 23.0. Armonk, NY: IBM Corp. The data were assessed using descriptive statistics such as the mean and percentage. The Wilcoxon–Mann–Whitney U-test was used to compare continuous variables in patient's characteristics between PNI-positive and PNI-negative groups, while Chi-square test was used to compare discrete variables in patient's characteristics between PNI-positive and PNI-negative groups. Two-tailed P < 0.05 was considered to be statistically significant.


 > Results Top


Patient's characteristics

Out of 1716 eligible patients, PNI was positive in 553 (32.2%) patients, while 1163 patients (67.7%) were PNI negative, as is depicted in [Table 1]. Majority of patients in PNI-positive group, i.e., 162 (29.2%), were in the age group of 40–49 years, while only 6 (1%) patients were in the age group of 80–89 years. Out of all PNI-positive patients, 446 (80.7%) patients were male and 107 (19.3%) patients were female. Among the PNI-positive patients, maximum number, i.e., 204 (36.9%), of patients had carcinoma of buccal mucosa, followed by carcinoma of tongue 161 (29.1%). Ulcero-infiltrative lesion was the most common gross appearance of the primary in PNI-positive cases constituting 376 (68.1%) patients and only 4 (0.7%) patients had verrucous type of lesion. In PNI-positive patients, most of the patients, i.e., 254 (45.9%), had Grade II disease and only 118 (21.3%) patients had Grade I disease. Patients with Stage IVA were highest, i.e., 228 (41.3%), in the PNI-positive group, while the lowest number of patients, i.e., 53 (9.5%) had Stage I disease.
Table 1: Clinicopathological parameters in 553 peri-neural invasion-positive patients

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Comparison between peri-neural invasion-positive and peri-neural invasion-negative patients

PNI-positive patients had a mean age of presentation of 48.76 ± 12.42, but it was 51.52 ± 12.51 in PNI-negative patients, as reflected in [Table 2]. The largest cervical lymph node size was 1.55 ± 0.55 cm in PNI-positive patients, whereas it was 1.41 ± 0.48 cm in PNI-negative patients. Maximum tumor (T) size was 3.14 ± 1.20 cm in PNI-positive group, whereas T size was 2.78 ± 1.22 cm in PNI-negative group. DOI was 10.57 ± 3.99 in PNI-positive patients, whereas it was 7.64 ± 4.25 cm in PNI-negative patients. LVSI positivity was seen in 60 (10.84%) PNI-positive patients, whereas 51 (4.38%) PNI-negative patients had LVSI positive. Lymph node positive was seen in 305 (55.13%) PNI-positive patients, in contrast to that, 358 (30.78%) PNI-negative patients presented with lymph node positivity. ENE was presented in 13 (2.3%) patients among PNI-positive group, whereas 13 (1.1%) patients were ENE positive among PNI-negative group.
Table 2: Comparison of various clinicopathological parameters in 553 peri-neural invasion-positive patients with 1163 peri-neural invasion-negative patients

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 > Discussion Top


PNI as an independent risk factor associated with increased incidence of locoregional recurrence, distant metastasis, and decreased 5 years' overall survival.[6],[7] It reflects the face of biology of OSCC.

PNI is defined as the presence of tumor cells in close proximity to the nerve and involving at least 33% of its circumference or tumor cells within any of 3 layers that is epineurium, endoneurium, and perineurium of nerve sheath.[8] According to Rahima et al.,[9] PNI is defined as positive when there is presence of tumor cells in perineural space or epineurium. The incidence of PNI in OSCC varies from 2.5% to 71%.[10] Due to the activation of neurotrophic growth factor and its receptor TrkA at perineural space, the tumor cells grow and proliferate at perineural space.[6],[8] PNI can present as different patterns, i.e., complete encirclement of perineurium by cancer cells (onion bulb like), partial covering of the perineurium (crescent like), or rarely cancer cells distributed in endoneurium.[9]

Besides hematogenous and lymphatic spread, PNI represents as the third route of dissemination of tumor cells in OSCC.

The incidence of PNI in OSCC ranges from 2.5% to 71%. According to Deepthi et al.,[11] the incidence of PNI was 45.27%. In a similar study by Varsha et al.,[12] the incidence of PNI was 40.5%. In the present study, the incidence of PNI was 33.2%. In a study conducted by Alkhadar et al.,[13] the mean age of presentation in PNI-positive patients was 68.8 ± 12 years and 73.3 ± 12.1 years in PNI-negative patients. In comparison to the above study, the mean age of presentation in the present study was 48.76 ± 12.42 in PNI-positive group and 51.52 ± 12.51 in PNI-negative patients. Majority of patients were in the age group of 40–59 years comprising 296 (53.4%) patients. In this study, majority of patients presented at an early age which implied the aggressiveness of disease in younger age group. Various authors have reported that there is no sex predilection in PNI-positive patients.[11],[13] But in the present series, male predominance was observed, i.e., 446 (80.7%) patients were male and 107 (19.3%) patients were female. The possible explanation for the male predominance and young age of presentation was due to lifestyle, i.e., more consumption of tobacco among the male patients.

The prevalence of PNI positivity in different sites of oral cavity varies from author to author. Carcinoma tongue and floor of mouth represent the most common site of primary in PNI-positive patients of OSCC.[10],[13] But in the present study, carcinoma buccal mucosa was the most common primary site of PNI-positive OSCC constituting 204 (36.9%) patients followed by carcinoma tongue 161 (29.1%) patients.

The incidence of PNI positivity depends on the grade of OSCC. According to Varsha et al.,[12] PNI was common in moderately differentiated squamous cell carcinoma (SCC), i.e., Grade II. In contrast, Manjula et al.[14] reported that PNI was more common in poorly differentiated SCC, i.e., Grade III. But in the present series, maximum number, i.e., 254 (45.9%), PNI-positive patients had Grade II disease followed by Grade III 181 (32.8%) and only 118 (21.3%) patients had Grade I disease and was consistent with the findings by Varsha et al.[12]

In AJCC 8th edition, DOI along with the T size has been incorporated for T category in TNM staging of OSCC. DOI of 5 mm is an independent prognostic factor. Alkhadar et al.[13] reported that the percentage of PNI positivity was 61.3% when DOI was more than 4 mm, whereas it was 13.3% when DOI was <4 mm in OSCC. In the present study, the mean DOI was 10.57 mm ± 3.9 mm in PNI-positive group and 7.64 ± 4.2 mm in PNI-negative group. It was observed that as DOI increases, the incidence of PNI also increases. In our study, majority of the primary lesion was in buccal mucosa which might be the possible explanation for higher DOI, i.e., 10.57 mm ± 3.9 mm in PNI-positive group.

Wallwork et al.[15] revealed that there is no association between PNI and nodal status. In contrast, other authors, i.e., Miller et al.,[7] Varsha et al.,[12] and Larsen et al.,[16] found a significant association between PNI and lymph node metastasis. In our study, 305 (55.13%) patients had positive lymph nodes in PNI-positive group, whereas 358 (30.78%) patients presented with positive lymph nodes in PNI-negative group. In the present study, the strength of association between PNI and positive lymph node is strong and PNI is a good predictor of nodal metastasis. Alkhadar et al.[13] reported that the incidence of ENE was 26.7% in patients having positive PNI and 9.3% in PNI-negative patients. The present study also affirms that the incidence of ENE is more in patients having PNI versus PNI-negative patients, i.e., 2.3% versus 1.1%, respectively.

LVSI is established when there is the presence of neoplastic cells in the wall or lumen of blood and lymphatic vessel. Its correlation with a lower rate of survival and high risk of recurrence is evident.[17] However, its relation with PNI is not well established due to the paucity of literature. In our study, 60 (10.84%) patients of PNI-positive group also had LVSI positivity, whereas 51 (4.38%) patients had LVSI positivity in PNI-negative group.

Deepthi et al.[11] revealed that the incidence of PNI differs in different stages. At the advanced stage of the disease, the incidence of PNI is much more evident and may be one of the important factors that guides the clinicians to take the decision for adjuvant treatment. In the present study, patients with PNI positive had a maximum tumor size of 3.14 ± 1.20 cm, whereas in PNI-negative patients, it was 2.78 ± 1.22 cm. In this study, 228 (41.3%) patients were in Stage IVA, 142 (25.7%) patients in Stage II, and 130 (23.5%) patients presented in Stage III in PNI-positive group of patients. Hence, as the tumor size increases or stage of the disease increases, the incidence of PNI also increases.

Limitation of the study

The fallacy of the present study is that this study has reported only PNI, but the type of nerve involvement (large or small) and extent of neural involvement have not been analyzed. Further, this was a retrospective analysis on 1716 patients of OSCC who had been analyzed in a single institution and thus these data cannot be generalized to the whole population.


 > Conclusion Top


PNI represents the third route of spread in OSCC besides hematogenous and lymphatic spread. It is one of the adverse prognostic factors. Various histopathological findings such as tumor location, tumor size, grade of tumor, DOI, LVSI, lymph node involvement, and advanced stage of OSCC are responsible for PNI positivity. Hence, PNI should be assessed in all histopathology reports of OSCC because it guides clinicians regarding adjuvant treatment in early OSCC.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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Miller ME, Palla B, Chen Q, Elashoff DA, Abemayor E, St John MA, et al. A novel classification system for perineural invasion in noncutaneous head and neck squamous cell carcinoma: Histologic subcategories and patient outcomes. Am J Otolaryngol 2012;33:212-5.  Back to cited text no. 7
    
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    Figures

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    Tables

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