Molecular and Cellular Mechanisms of Perineural Invasion in Oral Squamous Cell Carcinoma: Potential Targets for Therapeutic Intervention

The most common oral cavity cancer is squamous cell carcinoma (SCC), of which perineural invasion (PNI) is a significant prognostic factor associated with decreased survival and an increased rate of locoregional recurrence. In the classical theory of PNI, cancer was believed to invade nerves directly through the path of least resistance in the perineural space; however, more recent evidence suggests that PNI requires reciprocal signaling interactions between tumor cells and nerve components, particularly Schwann cells. Specifically, head and neck SCC can express neurotrophins and neurotrophin receptors that may contribute to cancer migration towards nerves, PNI, and neuritogenesis towards cancer. Through reciprocal signaling, recent studies also suggest that Schwann cells may play an important role in promoting PNI by migrating toward cancer cells, intercalating, and dispersing cancer, and facilitating cancer migration toward nerves. The interactions of neurotrophins with their high affinity receptors is a new area of interest in the development of pharmaceutical therapies for many types of cancer. In this comprehensive review, we discuss diagnosis and treatment of oral cavity SCC, how PNI affects locoregional recurrence and survival, and the impact of adjuvant therapies on tumors with PNI. We also describe the molecular and cellular mechanisms associated with PNI, including the expression of neurotrophins and their receptors, and highlight potential targets for therapeutic intervention for PNI in oral SCC.

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The Length of Peri-Neural Spreading in Clinically Mandibular Invaded Oral Cavity Squamous Cell Carcinoma

Journal of the Medical Association of Thailand ◽

10.35755/jmedassocthai.2020.05. ◽

2020 ◽

pp. 459-464

Keyword(s):

Squamous Cell Carcinoma ◽

Oral Cavity ◽

Cell Carcinoma ◽

Squamous Cell ◽

Lymphovascular Invasion ◽

Perineural Invasion ◽

Inferior Alveolar Nerve ◽

Surgical Margin ◽

Neural Invasion ◽

Resected Margin

Background: The objective of surgical management of oral squamous cell carcinoma (OSCC) is adequate resection with a clear margin. However, there is still a debate as to the optimal length for a mandibular resected margin. Objective: To examine the length of peri-neural spreading in T4 mandibular invaded oral cavity squamous cell carcinoma. Materials and Methods: Twenty-eight T4 pathological OSCC specimens that involved mandible and serial slices were studied and the length of tumor spreading along the inferior alveolar nerve (IAN) was determined. Tumor characteristics, risk factors, and survival were analyzed. Results: The incidence of peri-neural invasion was 11.11%, and IAN invasion was found in 14.29% of the tumor-invaded mandibular marrow. The length of tumor spreading along IAN was 3 to 12 mm. Poor prognostic factors of T4 OSCC were it being located on the tongue (HR 14.16), was pathological N2-3 (HR 31.05), and had high-risk features such as peri-neural invasion, lymphovascular invasion, and extra-nodal extension. Conclusion: A mandibular resected margin of at least 18 mm is recommended as a clear surgical margin in cases of T4 mandibular invasion OSCC. Keywords: Oral cancer, Perineural invasion, Inferior alveolar nerve, Squamous cell carcinoma, Mandibulectomy

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Perineural and Vascular Invasion in Oral Cavity Squamous Carcinoma: Increased Incidence on Re-review of Slides and by Using Immunohistochemical Enhancement

Archives of Pathology & Laboratory Medicine ◽

10.5858/2005-129-354-paviio ◽

2005 ◽

Vol 129 (3) ◽

pp. 354-359 ◽

Cited By ~ 12

Author(s):

Kevin A. Kurtz ◽

Henry T. Hoffman ◽

M. Bridget Zimmerman ◽

Robert A. Robinson

Keyword(s):

Squamous Cell Carcinoma ◽

Oral Cavity ◽

Cell Carcinoma ◽

Squamous Cell ◽

Vascular Invasion ◽

Perineural Invasion ◽

False Negative ◽

Squamous Carcinoma ◽

Pathology Report ◽

Negative Results

Abstract Context.—Perineural invasion and vascular invasion may be adverse prognostic factors in patients with oral cavity squamous cell carcinoma. However, the incidence of perineural and vascular invasion varies in the literature, and the use of immunohistochemistry to enhance their detection has not been evaluated in oral cavity squamous cell carcinomas. Objective.—To determine if the previously assessed incidence of perineural and vascular invasion in cases of oral cavity squamous cell carcinoma would be increased by re-review of the original routinely hematoxylin-eosin–stained sections as well as review of slides stained immunohistochemically with S100 and CD31 to enhance visualization of nerves and vessels. Design.—Forty cases of oral cavity squamous cell carcinoma in which the status of perineural and vascular invasion had been part of the original pathology report were reviewed. All original routinely stained slides were reviewed as well as S100- and CD31-stained sections of each case's tissue blocks that contained tumor. Results.—Perineural invasion was identified in 30% (12/ 40) of tumors in the original reports, 62% (25/40) of the authors' re-review of the same slides, and 82% (33/40) when cases were stained with S100. Vascular invasion was identified in 30% (12/40) of tumors in the original reports, 35% (14/40) of the authors' re-review of the same slides, and 42% (17/40) when cases were stained with CD31. False-positive and false-negative results were common in the original reports. The number of foci of both types of invasion was related to its discovery in the original reports. Vascular invasion, but not perineural invasion, was significantly associated with death at 5-year follow-up. Conclusions.—Although careful re-review of routinely stained slides will detect a significant number of cases of perineural and vascular invasion, immunohistochemical enhancement further improves the accuracy of the determination.

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Prognostic impact of extratumoral perineural invasion in patients with oral cavity squamous cell carcinoma

Cancer Medicine ◽

10.1002/cam4.2392 ◽

2019 ◽

Vol 8 (14) ◽

pp. 6185-6194 ◽

Cited By ~ 1

Author(s):

Li‐Yu Lee ◽

Dante De Paz ◽

Chien‐Yu Lin ◽

Kang‐Hsing Fan ◽

Hung‐Ming Wang ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Oral Cavity ◽

Cell Carcinoma ◽

Squamous Cell ◽

Perineural Invasion ◽

Prognostic Impact

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Impact of Perineural Invasion in the Pathologically N0 Neck in Oral Cavity Squamous Cell Carcinoma

Otolaryngology ◽

10.1177/0194599813506867 ◽

2013 ◽

Vol 149 (6) ◽

pp. 893-899 ◽

Cited By ~ 54

Author(s):

Steven B. Chinn ◽

Matthew E. Spector ◽

Emily L. Bellile ◽

Jonathan B. McHugh ◽

Thomas J. Gernon ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Oral Cavity ◽

Cell Carcinoma ◽

Squamous Cell ◽

Perineural Invasion ◽

N0 Neck

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S096 Nomogram for Predicting Locoregional Recurrence-Free Survival After Treatment of Oral Cavity Squamous Cell Carcinoma

Archives of Otolaryngology - Head and Neck Surgery ◽

10.1001/archotol.132.8.860-b ◽

2006 ◽

Vol 132 (8) ◽

pp. 860

Author(s):

N. D. Gross ◽

S. G. Patel ◽

A. L. Carvalho ◽

P. Chu ◽

L. P. Kowalski ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Oral Cavity ◽

Cell Carcinoma ◽

Squamous Cell ◽

Locoregional Recurrence ◽

Recurrence Free Survival ◽

Free Survival

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Perineural Invasion in Squamous Cell Carcinoma of the Oral Cavity: Histology, Tumor Stage, and Outcome

Laryngoscope Investigative Otolaryngology ◽

10.1002/lio2.4 ◽

2016 ◽

Vol 1 (1) ◽

pp. 13-18 ◽

Cited By ~ 7

Author(s):

Roman D. Laske ◽

Irene Scholz ◽

Kristian Ikenberg ◽

Christian Meerwein ◽

Domenic G. Vital ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Oral Cavity ◽

Cell Carcinoma ◽

Squamous Cell ◽

Perineural Invasion ◽

Tumor Stage

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Predictive scoring systems for distant metastases in oral cavity squamous cell carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e18536 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e18536-e18536

Author(s):

Hsueh Ju LU ◽

Kuan-Ming Lai ◽

Chih-Yu Peng ◽

Hsien-Chun Tseng ◽

Chung-Han Hsin ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Oral Cavity ◽

Cell Carcinoma ◽

Squamous Cell ◽

Locoregional Recurrence ◽

Surgical Margin ◽

Scoring Systems ◽

Distant Metastases ◽

Initial Diagnosis ◽

University Hospital

e18536 Background: At least 10% of patients with oral cavity squamous cell carcinoma (OCSCC) would progress to distant metastases (DM). Median overall survival (OS) after distant metastases is only one year and rare biomarkers are available to predict distant metastatic events. Methods: A total of 595 OCSCC patients who underwent curative surgical resection at Chung Shan Medical University Hospital were enrolled from Jan 2010 to Dec 2016. The clinical–pathological variables were compared using the χ2 test. Cox proportional-hazards analyses were performed for distant metastatic free survival (DMFS), defined from the date of initial diagnosis to the date of distant metastasis. Two scoring systems for predicting distant metastases were established for patients with pathologic regional lymph node –positive (pN+) or –negative (pN–), separately. Results: Nearly 10% (8.9%, 53/595) of patients with OCSCC would progress to DM during follow-up [20.6% (28/136) and 5.4% (25/459) for patients with pN+ and pN–, respectively]. Most of the distant metastatic lesions developed within 3 years after initial diagnosis (overall, 84.9%, 45/53; patients with pN+, 92.9%, 26/28; patients with pN–, 76.0%, 19/25). For patients with pN+, rapidly locoregional recurrence (≦6 months), lymphovascular invasion, and lymphocyte-monocyte ratio(<2.5) were the independent factors for DMFS. In addition, rapidly locoregional recurrence, elderly (age > 65), and close surgical margin(≦5mm) were independent for those with pN–. If each of the independent factors was scored one point to predict DM occurring within 3 years after the initial diagnosis, two scoring systems were established for the corresponding patients with pN+ or pN–, separately. The area under the curves of these two scoring systems for the corresponding patients with pN+ and pN– were 0.737 and 0.825, respectively (Table). Conclusions: The established scoring systems effectively predict distant metastases for OCSCC patients. [Table: see text]

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Prognostic Value of Perineural Invasion in Oral Tongue Squamous Cell Carcinoma: A Systematic Review and Meta-Analysis

Frontiers in Oncology ◽

10.3389/fonc.2021.683825 ◽

2021 ◽

Vol 11 ◽

Author(s):

Jiajia Li ◽

Shan Liu ◽

Zhangao Li ◽

Xinxin Han ◽

Lin Que

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Locoregional Recurrence ◽

Perineural Invasion ◽

Early Stage ◽

Tongue Squamous Cell Carcinoma ◽

Sensitivity Analyses ◽

Cochrane Library ◽

Oral Tongue

ObjectivesA significant number of recently published research has outlined the contribution of perineural invasion (PNI) to clinical outcomes in oral tongue squamous cell carcinoma (OTSCC), but some results remain conflicting. This study aimed to determine whether patients with OTSCC with PNI have a worse prognosis than those without PNI.Materials and MethodsPubMed, Embase, and the Cochrane Library were queried for potentially eligible articles published up to December 2020. The primary outcomes were the hazard ratio (HR) for locoregional recurrence, overall survival (OS), disease-free survival (DFS), and cancer-specific survival (CSS). The random-effect model was used in all analyses.ResultsSeventeen studies (4445 patients) were included. Using adjusted HRs, the presence of PNI was associated with a higher risk of locoregional recurrence (HR=1.73, 95%CI: 1.07-2.79, P=0.025, I2 = 33.1%, Pheterogeneity=0.224), worse OS (HR=1.94, 95%CI: 1.39-2.72, P<0.001, I2 = 0.0%, Pheterogeneity=0.838), worse DFS (HR=2.13, 95%CI: 1.53-2.96, P<0.001, I2 = 48.4%, Pheterogeneity=0.071), and worse CSS (HR=1.93, 95%CI: 1.40-2.65, P<0.001, I2 = 25.5%, Pheterogeneity=0.251). PNI had an impact on locoregional recurrence in early-stage OTSCC but not in all stages, and on OS, DFS, and CSS in all-stage and early-stage OTSCC. The sensitivity analyses showed that the results were robust.ConclusionThe presence of PNI significantly affects the locoregional recurrence and survival outcomes among patients with OTSCC.

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