Vascular and neural invasion in oral squamous cell carcinoma: A study in an Iranian population
Nakisa Torabinia1, Gholamreza Jahanshahi2, Vahid Eslami3, Forooz Keshani2
1 Department of Oral and Maxillofacial Pathology, Dental Materials Research Center, Dental Research Institute, School of Dentistry, Isfahan University of Medical Sciences, Isfahan, Iran
2 Department of Oral and Maxillofacial Pathology, Dental Research Center, Dental Research Institute, School of Dentistry, Isfahan University of Medical Sciences, Isfahan, Iran
3 Department of Oral and Maxillofacial Pathology, School of Dentistry, Isfahan University of Medical Sciences, Isfahan, Iran
|Date of Submission||24-Jul-2021|
|Date of Acceptance||12-Dec-2021|
|Date of Web Publication||28-Mar-2023|
Dr. Forooz Keshani
Department of Oral and Maxillofacial Pathology, Dental Research Center, Dental Research Institute, School of Dentistry, Isfahan University of Medical Sciences, Isfahan
Source of Support: None, Conflict of Interest: None
Background: Among various parameters used to predict the outcome of malignancy, nerve invasion has been widely considered as a sign of aggressive behavior in oral cancers. According to the importance of neural invasion in predicting the outcome of oral squamous cell carcinoma (OSCC), this study aimed to evaluate the prevalence of neural and vascular invasion in OSCC.
Materials and Methods: In this descriptive, analytical, and cross-sectional study, paraffin-embedded tissues of 62 OSCC in the health center of surgery and pathology were evaluated (2013–2015). Patients' archives were evaluated and recorded in terms of their age and gender. Hematoxylin and eosin (H&E) slides were then examined by two oral pathologists and scrutinized for the presence of nerve involvement, tumor differentiation, vascular and lymph node invasion, and depth of invasion. Data were analyzed using SPSS version 23, t-test, and one-way ANOVA (P < 0.05).
Results: Of 62 tumors, 12 patients showed only nerve invasion, 17 cases had only vascular invasion, and seven patients had both neural and vascular invasion, simultaneously, known as a neurovascular invasion. Furthermore, there was no vascular and neural invasion in 26 cases. There was a statistically significant correlation between vascular and neural invasion and the tumor site (P = 0.045). The highest frequency of neural invasion, as well as vascular invasion, was related to tongue tumors.
Conclusion: The relation between neural and vascular invasion in OSCC with tumor's location was statistically significant. Lip and tongue carcinoma had shown more neurovascular invasion without relation to gender, age, and cell differentiation.
Keywords: Cell differentiation, prognosis, squamous cell carcinoma
|How to cite this article:|
Torabinia N, Jahanshahi G, Eslami V, Keshani F. Vascular and neural invasion in oral squamous cell carcinoma: A study in an Iranian population. Adv Biomed Res 2023;12:70
|How to cite this URL:|
Torabinia N, Jahanshahi G, Eslami V, Keshani F. Vascular and neural invasion in oral squamous cell carcinoma: A study in an Iranian population. Adv Biomed Res [serial online] 2023 [cited 2023 Jun 7];12:70. Available from: https://www.advbiores.net/text.asp?2023/12/1/70/372578
| Introduction|| |
Oral squamous cell carcinoma (OSCC) consists of 90% of all oral cavity malignancy., OSCC can invade adjacent tissues and cervical lymph nodes. However, it rarely has distant metastasis. The prognosis of OSCC could be affected by various parameters. Neural invasion is one of the indicators for determining the aggressive behavior of this tumor. Perineural invasion (PNI), tumoral cell growth around the neural fascicles, is reported by 2%–30% of head-and-neck carcinoma in the literatures.,, In fact, this is one of the pathways of tumoral progression and metastasis that is similar yet distinct from vascular and lymphatic invasion. It is of notice that this invasion is often overlooked during surgery.
Therefore, the presence of PNI as a prognostic factor affecting therapeutic decisions, recurrence, and distant metastases should be checked in each OSCC. It requires more aggressive treatment and control of lymph nodes and adjuvant therapies. Nerve invasions are associated with a high probability of regional and distant metastases, a greater depth of tumor invasion, less differentiation, and a lower 5-year survival rate.
The study by Varsha et al. in 2015 showed that the prevalence of PNI in OSCC is more than 40%, which can be seen in primary and recurrent tumors regardless of its histopathologic grading. Yang et al., In their 2018 study, introduced an invasion around the nerve as a histopathologic and clinical feature associated with aggressive and poor prognosis, and suggested that better understanding of this process could increase the therapeutic factors for this disease. Siddiqui et al. described clear relation between the presence of vascular invasion and increased probability of regional and distant metastasis, as well as a reduction in the survival of 5 years.
Carter et al., in their study, identified neural involvement with a diameter <0.1 mm is related to poor prognosis without other risk factors, and found that involvement of larger diameter neuron is associated with an increased risk of lymph nodes metastasis and death.
In 2017, Chatzistefanou et al. introduced the PNI as a strong index for the determination of poor prognosis in patients with oral cancer. They showed a strong association between PNI and tumor invasion, recurrence of disease, and increased mortality in patients.
Faisal Wallwork et al. in 2007 did not find a meaningful relation between neural invasion, tumor differentiationdepth, and the presence of lymph nodes metastasis in the floor of mouth cancer. However, the majority of studies confirm the association between neural invasion and the ability of neck region's lymph nodes invasion that should be considered in treatment,,, but so far, no study has been done in Iran about the rate of neural invasion and its association with prognosis of OSCC. Therefore, considering the importance of neural invasion in the prognosis of OSCC and its treatment plan, this study evaluated the prevalence of neural and vascular invasion in OSCC in Iran.
| Materials and Methods|| |
This cross-sectional, descriptive, and analytical study was done in dental school, Isfahan University of Medical Sciences, between 2013 and 2015. The study samples were 62 patients with OSCC, which were selected from all available patients who had undergone an excisional surgical diagnosis of OSCC in Isfahan clinics in census mode.
The researcher, after the necessary coordination, reviewed the patients' archives and recorded their ages and gender. Paraffin blocks of samples were extracted and stained with hematoxylin and eosin (H and E). It is of note that those samples without sufficient tissue for staining or inadequate information were excluded. Then, they were examined with two oral pathologists under the light microscope (Olympus BX41TF, Tokyo, Japan) and evaluated for the presence of nerve involvement, tumor differentiation, vascular and lymph node invasion, and depth of invasion. In case of nerve involvement, its pattern was examined in two forms “Intraneural and perineural.” The PNI identified as tumor cells were seen in the perineural space. According to the Brian classification, pleomorphism in nucleus and number of mitosis, the degree of tumor differentiation was graded into a well, moderate, and poorly differentiation. Identification of tumor cells in endothelial canals was considered as a vascular and lymphatic invasion. The depth of invasion was determined by measuring the distance between the tumor surface and the deepest infiltration point via the graded lens. Considering the use of archives in this study, according to the Helsinki Treaty, there was no ethical limitation on the implementation of the plan.
The protocol was approved with the number 394847 by the Ethics and Research Committee of Isfahan University of Medical Sciences. The data were analyzed using statistical software, SPSS version 23 (IBM, Armonk, NY, United States of America), t-test, and one-way ANOVA.
| Results|| |
In this study, 62 patients with OSCC with a mean age of 59.7 ± 12.7 years were studied (41 [66.2%] were male and 21 [33.9%] were female). Most of these patients reported smoking (32 patients [51.6%]), some of them reported drinking alcohol (six patients [9.7%]) and 15 patients had systemic diseases (24.2%). The most common site of the tumor was the tongue with a frequency of 26 cases and a lip with an incidence of 16 cases. The frequency of involvement in other patients is shown in [Figure 1].
|Figure 1: Frequency of oral squamous cell carcinomas regarding their involvement site|
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Well-differentiated tumor cells were seen in 29 patients (46.8%), 17 patients had moderate differentiation (27.4%), and 16 cases had poorly differentiation (25.8%). Of 62 tumors studied, 12 patients (19.4%) showed only nerve invasion, 17 cases had (27.4%) only vascular invasion, seven patients (11.3%) had both neural and vascular invasion (neurovascular invasion), and there was no vascular and neural invasion in 26 cases (41.9%) [Figure 2]. The average depth of the invasion in tumors was 8.6 ± 3.9 mm (the minimum and maximum depth of the invasion was 2 and 15 mm, respectively). In addition, the depth of invasion was <5 mm in four patients (6.5%), 5–9 mm in 12 patients (19.4%), and more than 10 mm in 11 patients (17.7%). Fisher's exact test showed a statistically significant correlation between vascular and neural invasion and the tumor site (P = 0.045). The highest frequency of neural invasion, as well as vascular invasion, was related to tongue tumors (26.9%). In contrast, most neurovascular invasions were related to lip cancer (18.8%). It is of note that there were minimum invasions in the oropharyngeal region (55.6%).
|Figure 2: Frequency of invasion among samples of oral squamous cell carcinoma|
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There was a statistically significant relation between vascular and neural invasion and cell differentiation by Fisher's exact test (P < 0.001) [Table 1]. Most noninvasive tumors had poorly differentiated cells (87.5%), most of the tumors with neural invasion were well differentiated (27.6%), and all tumors with neurovascular invasion were well differentiated. t-test and one-way ANOVA did not show a statistically significant relation between the depth of tumor invasion and general characteristics of patients (age, gender, smoking, and alcohol drinking).
|Table 1: Relation between vascular and neural invasion and cell differentiation|
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| Discussion|| |
Oral cancer is one of the most important human malignancies. Squamous cell carcinoma accounts for about 80% of oral cancers. Although the prevalence of oral cancers is not high in comparison with other areas of the body, the increased risk factors for this disease during the last decade, such as smoking and alcohol, have led to a dramatic rise in the incidence of oral cancers. Several factors can affect the prognosis of squamous cell carcinomas, including tumor cell differentiation, tumor thickness, and vascular and neural invasion. Various articles have shown that vascular and PNI, especially nerve invasion (PNI), usually accompanied with a higher recurrence rate and mortality of patients.,, However, their exact pathogenesis is not clear yet. Nair et al. believed that vascular network, which is associated with the nerves, provides a nutritional agent for tumor cells growth. In general, it can be said that the involvement of the nerve is mainly indicated invasive activity of the tumor, which is sometimes ignored in histopathological reports, while it can be important in the treatment and recurrence of the cancers.
Since there were not enough studies about neurovascular invasions in OSCC, especially in Iran, this study evaluated the presence of neurovascular, neural, and vascular invasion and its association with tumor characteristics of 62 OSCC patients. The mean age of patients was 59.2 ± 12.7. Although the age pattern of oral cancer differs from country to country, the prevalence of oral cancer increases with age. In some studies, a higher incidence of neural invasion has been reported in younger patients., However, in the present study, there was no significant relationship between neurovascular invasion and age of the patients. Also in a study in Isfahan, in young people, there was no relation between the age of the patients and the grade of histopathology of OSCC. Hence, patients' age does not probably have much effect on the cellular differentiation, and therefore, the invasive behavior of the tumor cells.
In the present study, the samples were mostly male, with a ratio of 2-1. In the study of Matsushita et al., the ratio of men to women was 1.28. One study reported that male gender was one of the clinical factors associated with neural invasion, while in this study, there was no correlation between gender and neural inversion.
The most common site of OSCC in the present study was tongue and lips. There was a considerable relation between the presence of neural, vascular, and neurovascular invasion and tumor site (P = 0.045). The most neurovascular invasions were reported in the lips and tongue; by contrast, the lowest invasion was observed in the oropharyngeal tumors. This may be due to the higher incidence of OSCC in these areas or the presence of neurovascular plexus in these areas. It is also suggested that the tumor of this region is more invasive because of the greater presence of cervical lymph nodes in tongue tumors. Yang et al. also stated, in their study, the invasion to surrounding tissues is a problem of some squamous cell carcinoma, especially lip cancers. They said that lip cancers have a high rate of recurrence, invasive nerve circumference, difficulty in controlling, and even invasion into the skull through the alveolar, facial, and trigeminal nerves.
In this study, the highest incidence of neural, vascular, or neurovascular invasion was observed in well-differentiated tumors. This finding is contrary to other studies, including Chatzistefanou et al., which did not show a relation between tumor differentiation and invasion, and usually, squamous cell carcinomas with PNI have poorly differentiated cells. This difference is probably due to the higher differentiation of OSCC, which consists of almost half of the samples in this study, or because of the limitations of the present study.
The thickness of the tumor is also an important property of OSCC. In the present study, the thickness of the tumor was not significantly different in patients with neural invasion (5.63 mm) and without nerve invasion (4.93 mm). However, the mean thickness of the tumor was notably different in patients with vascular invasion (8.87 mm) and without an invasion (3.15 mm). Varsha et al. found a good relation between tumor thickness and nerve invasion. They suggested that high levels of PNI were observed in T2 and then T4, T3, and T1 stages. They reported that this result may be related to a low sample size in different groups.
According to the results of this study, tumor cells with deeper extension will have access to more vessels and may have more vascular invasion, whereas neural invasion depends on the molecular characteristics of the tumor cells, whether they tend to the nervous system or not. Although the depth of the microscopic invasion may be effective in the prognosis and spread of the tumor, it does not play a role in tumors' neural invasion.
Normally, the diagnosis of neurovascular invasion and neural invasion is difficult in histopathologic sections, especially when a large number of tumor cells invade the nerve. The presence of inflammation around the nerve and degeneration of the nervous system is highly likely to be a diagnostic key for tumor invasion. The bottom line is that the best way to survey the neural invasion is frozen sections, which can evaluate the large thickness of the tumor.
| Conclusion|| |
Based on the results of this study, there was a significant percentage of OSCC with neural and vascular invasion, which showed a statistically significant relation with tumor site. Lip and tongue carcinoma had shown more neurovascular invasion without relation to gender, age, and cell differentiation.
It is recommended to investigate the prevalence of oral cancers, especially squamous cell carcinoma, and the rate of neural and vascular invasion in the different geographic and racial regions. Furthermore, new methods for detecting neurovascular invasions and the treatment of these patients will be taught in retraining courses in the medical community who involved in the diagnosis and treatment of oral cancers. The results of this study will be considered in future studies, and the current results will be available to relevant units. It is suggested that a prospective study should elaborate on these parameters and their effects on prognosis.
Financial support and sponsorship
This study has been approved by research and ethics committee of Isfahan University of medical sciences and has been supported financially.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]