Skip to main content
NCBI home page
Advances in Dental Research logoLink to Advances in Dental Research
. 2019 Oct 21;30(2):45–49. doi: 10.1177/0022034519877388

Oral Cancer: Integration of Studies for Diagnostic and Therapeutic Precision

NJ D’Silva 1,2,✉, JS Gutkind 3,4
Editor: ME Ryan
PMCID: PMC6806126  PMID: 31633388

Abstract

Head and neck cancers are among the 10 most common cancers in the world and include cancers of the oral cavity, hypopharynx, larynx, nasopharynx, and oropharynx. At least 90% of head and neck cancers are squamous cell carcinomas (SCCs). This summary discusses the integration of clinical and mechanistic studies in achieving diagnostic and therapeutic precision in the context of oral cancer. Specifically, based on recent mechanistic studies, a subsequent study reevaluated current diagnostic criteria of perineural invasion in patients with oral cavity SCC showing that overall survival could be associated with nerve-tumor distance; validation of the findings of this study from a small group of patients could lead to a personalized approach to treatment selection in patients with oral cavity SCC. Moreover, delineation of key pathways in SCC revealed novel treatment targets that can be exploited to develop personalized treatment strategies to achieve long-term remission.

Keywords: squamous cell carcinoma, oral cavity, precision treatment, perineural invasion, immunotherapies, head and neck

Introduction

Head and neck cancers, are among the 10 most common cancers in the world (Leemans et al. 2018; Ferlay et al. 2019). Head and neck cancers include cancers of the oral cavity, hypopharynx, larynx, nasopharynx, and oropharynx. At least 90% of head and neck cancers (i.e., over 600,000 new cancers each year) are squamous cell carcinomas (SCCs) (Leemans et al. 2018; Ferlay et al. 2019). The 5-y survival rate of head and neck SCC (HNSCC) is ~40% to 50% (Leemans et al. 2018). However, patient survival significantly decreases once there is regional and/or distant tumor cell dissemination (Roberts et al. 2016). This supports the critical need for developing better diagnostic tools for perineural invasion, an important predictor of occult nodal involvement in HNSCC.

The oral cavity, including the lip, is the most common site of SCC in the head and neck region (Ettinger et al. 2019; Siegel et al. 2019). In the United States, the 2019 estimate of new cases of oral cavity SCC is 35,130 and the estimate of deaths from oral cavity SCC is 7,410 (Siegel et al. 2019). Locoregional recurrence occurs in patients treated for SCC and is associated with poor survival. Appropriate treatment selection for SCC requires an accurate diagnosis and identification of patients who are likely to develop recurrence. Pathologic features such as perineural invasion, extracapsular spread in the lymph node, lymphovascular invasion, and status of the resection margin are informative in identifying patients who are at risk for locoregional recurrence (Safi et al. 2017). The focus of the diagnosis section of this review will be on perineural invasion in oral cavity SCC. Precision medicine is the use of molecular profiling to customize treatment for each individual patient (El-Deiry et al. 2019). In the section on precision treatment (medicine), current and emerging new treatment options for oral cavity and oropharyngeal SCC will be discussed.

Precision Diagnosis

Oral cavity SCCs usually arise from the lining epithelium of the oral mucosa. Clinically, oral cavity SCCs present as leukoplakias, erythroplakias, or exophytic or endophytic lesions, with or without ulceration and induration. Oral cavity SCCs originate from keratinocytes, which comprise the surface epithelium of the oral mucosa. From the surface epithelium, transformed keratinocytes invade the underlying tissue after destruction of the basement membrane that separates the epithelium from the connective tissue. Histopathologic examination of SCC shows malignant neoplastic cells that are arranged in islands and nests of varying size, cords, and single cells, within the connective tissue. From the connective tissue, malignant neoplastic cells can spread to adjacent and distant sites (metastases) via direct extension, nerves, blood vessels, and lymphatics.

Diagnostic Significance of Perineural Invasion

Pathologic features in oral cavity SCC have a role in treatment selection. Oral cavity SCC is usually treated with surgery; radiation or chemoradiation may be used as adjuvant therapy if adverse histopathologic criteria such as perineural invasion or nodal disease are detected (Ettinger et al. 2019).

Lymph node involvement, including extracapsular spread, is associated with poor outcome in oral cavity SCC (Ettinger et al. 2019). In fact, the most recent edition (eighth) of the manual of the American Joint Committee on Cancer includes extranodal extension for N staging of tumors (reviewed in Ettinger et al. 2019). Almost one-third of patients with oral cavity SCC have occult lymph node involvement (i.e., it is not detected on clinical exam) (Ettinger et al. 2019). Perineural invasion is an important predictor of occult nodal involvement in oral cavity SCC (Sparano et al. 2004) and has been associated with recurrence in lymph nodes. Consequently, patients with a tumor that exhibits perineural invasion are treated with lymph node dissection and/or radiation and potentially chemotherapy (Tai et al. 2012; Chinn et al. 2013). In addition, perineural invasion is an independent risk factor for poor prognosis (Chinn et al. 2013). Therefore, an accurate diagnosis of perineural invasion is important for planning elective lymph node dissections and for selection of adjuvant treatment.

Although survival of early stage SCC is better than late-stage SCC, 13% to 33% of patients with early stage oral cavity SCC die of disease (Sessions et al. 2002; Jerjes et al. 2011). To identify those patients with early stage cancers who are at greater risk for treatment failure, histologic risk models have been proposed. These models include perineural invasion, depth of invasion, worst pattern of invasion, and lymphocytic host response (Brandwein-Gensler et al. 2010).

Perineural invasion in SCC is associated with an increased risk of metastasis and poor survival (reviewed in Schmitd, Scanlon, et al. 2018), also highlighting the importance of detecting this phenotype.

Defining Perineural Invasion

SCC is a cancer that is attracted to nerves (i.e., it is neurotropic) (Binmadi and Basile 2011). The first report of tumor growing along nerves was in 1835 (Cruveilhier 1835). Subsequently, Batsakis defined neural or perineural invasion as cancer “within, around or through the nerve” (Batsakis 1985). The current definition of perineural invasion proposed by Liebig et al. (2009) is “tumor within, in close proximity to and surrounding at least a third of the nerve” (Fig. 1) and is subject to interpretation.

Figure 1.

Figure 1.

Open in a new tab

Perineural invasion: cancer cells within, partially, or completely surrounding the nerve.

Perineural invasion has been reported in 5.2% to 90% of SCCs (reviewed in Schmitd, Scanlon, et al. 2018). This wide range across multiple studies may be due to variable criteria; some studies define the criteria used, whereas others do not (reviewed in Schmitd, Scanlon, et al. 2018). In addition, retrospective studies of perineural invasion in SCCs that extract information from pathology reports rather than from review of pathology slides may show variations due to when the diagnosis was made and do not reflect the evolution of the definition of perineural invasion. Furthermore, although immunohistochemistry enhances detection of perineural invasion, it is not used routinely to detect perineural invasion (Shen et al. 2014; Schmitd, Beesley, et al. 2018), which may contribute to variations in detection.

Although it is apparent that an accurate diagnosis of perineural invasion is important for treatment of SCC, using current subjective criteria, there is only moderate agreement among pathologists in diagnosing perineural invasion in SCC (Chi et al. 2016). Objective diagnostic criteria would facilitate diagnosis of perineural invasion and appropriate treatment selection.

Perineural Invasion Is a Dynamic Process

Revisiting the diagnostic criteria in perineural invasion may be appropriate given the findings of recent mechanistic studies. Although the nerves were considered passive bystanders in the process of perineural invasion, more recent studies have shown dynamic communication between cancer and nerves during perineural invasion (Ayala et al. 2008; Scanlon et al. 2015). For example, in coculture experiments, galanin released by dorsal root ganglia induces SCC cells to release cytokines that promote neuritogenesis and invasion of cancer cells (Scanlon et al. 2015). In a subsequent study, Lin et al. (2017) showed that glial cell line–derived neurotrophic factor released by dorsal root ganglia promoted perineural invasion. Importantly, these recent mechanistic studies in SCC show that biochemical crosstalk occurs prior to physical contact between the SCC and neurites (Scanlon et al. 2015; Lin et al. 2017). However, the current definition of perineural invasion (i.e., “tumor within, in close proximity to, and surrounding at least a third of the nerve”) (Liebig et al. 2009) implies that the nerve and cancer should be physically contacting each other to be defined as perineural invasion. Therefore, a recent study investigated the association of nerve-tumor distance and patient survival (Schmitd, Beesley, et al. 2018). This retrospective study in patients with oral cavity SCC showed that overall survival was associated with nerve-tumor distance; as the latter increased, the relative death rate decreased. The study showed that the decrease in death rate was gradual from distance equal to zero, stabilizing at a distance of approximately 500 µm (Schmitd, Beesley, et al. 2018); biochemical interactions could occur within this distance. These findings suggest that a small distance between the nerve and tumor in oral cavity SCCs that would currently be defined as “perineural invasion negative” could be related to worse overall survival. Given the importance of perineural invasion in the diagnosis, treatment, and outcome of oral cavity SCC, validation of the findings of this study from a small group of patients could lead to a personalized approach to treatment selection in patients with oral cavity SCC.

Precision Treatment

Current Treatment Options for Oral Cancer

Most patients with oral cavity and oropharyngeal SCC initially present with locally advanced disease, which often requires a multidisciplinary approach involving surgery, radiation, and/or chemotherapy (Ang 2008). Surgery plays a key role, both at early stages as well as in locally advanced or recurrent disease. However, most surgeries involving large tumor resections are disfiguring and result in many undesirable effects for the patients, some of which can be mitigated by new surgical approaches. Surgery may not be sufficient to eradicate locally advanced SCC; often the initial surgery is followed by radiation therapy, using conventional approaches, altered fractionated schedules, and/or accelerated fractionation and intensity-modulated radiation therapy (Mendenhall et al. 2006). Chemotherapy is usually limited to advanced disease and in conjunction with radiation in patients who are at high risk of recurrence, including patients with residual disease (positive margins or unresectable SCC) and distant metastasis or extracapsular spread in locoregional lymph nodes (Bernier et al. 2005). The most frequently used chemotherapies include 5-fluorouracil, carboplatin or cisplatin, and taxol-based therapies and irinotecan in the most advanced cases. All of these approaches have a myriad of side effects, and despite aggressive, combined modality treatment, a significant proportion of patients will develop recurrent or metastatic disease that is no longer amenable to curative therapy (Ang et al. 2014) and die within a year of diagnosis of recurrent/metastatic oral cavity SCC (Vermorken et al. 2008; Ferris et al. 2016). The epidermal growth factor receptor (EGFR) is often expressed in oral SCC, and its expression is associated with poor outcome (Chung et al. 2006). Cetuximab, a monoclonal antibody targeted against EGFR, offers greater locoregional control in combination with radiotherapy in locally advanced tumors (Bonner et al. 2010), but as discussed below, many tumors ultimately become resistant to anti-EGFR therapy. There is an urgent need for novel therapeutic approaches to prevent and treat oral cavity and oropharyngeal SCC.

The Landscape of Genomic Alterations in SCC

The development of next-generation sequencing approaches and multiple cancer genome sequencing initiatives have revolutionized our understanding of cancer. Among them, the National Cancer Institute launched the Cancer Genome Atlas more than a decade ago together with multiple partnering institutes of the National Institutes of Health, including the National Institute of Dental and Craniofacial Research. The goal of the Cancer Genome Atlas is to provide a comprehensive, publicly available database of large-scale genome sequencing analyses through multiple omics platforms for a variety of cancer types (Hoadley et al. 2018). In the case of oral cavity and oropharyngeal SCC, more than 500 individual lesions were sequenced by the Cancer Genome Atlas, which revealed a remarkable multiplicity and diversity of genetic alterations (Cancer Genome Atlas Network 2015). The emerging results from the in-depth analysis of the oral and oropharyngeal cancer oncogenome suggest that while each individual tumor harbors distinct molecular alterations, they all participate in only a few molecular networks, including those regulated by the TP53, FAT1, NOTCH1, CASP8, and CDKN2A (p16INK4A) genes and PI3K mutations. Regarding the latter, PIK3CA, which encodes the PI3Kα catalytic subunit, is the most commonly mutated oncogene in oral cavity and oropharyngeal SCC in general (~20%), which is even higher in human papillomavirus (HPV)–positive oropharyngeal SCC lesions (25%) (Cancer Genome Atlas Network 2015).

Emerging Precision Therapeutic Options for SCC Prevention and Treatment

The oncogenome findings can explain the initial discovery that most SCC lesions exhibit persistent activation of the PI3K/mTOR pathway, which represents one of the most frequently dysregulated molecular mechanisms involved in growth promotion in oral cavity and oropharyngeal SCC (>80% of all HPV16– and HPV16+ cases (Molinolo et al. 2007; Molinolo et al. 2012). Aligned with the cancer-driving role of the PI3K/mTOR pathway, mTOR inhibitors were shown to exert potent antitumor activity in multiple experimental oral cavity SCC model systems (Czerninski et al. 2009; Molinolo et al. 2012). These findings provided the rationale for launching a multi-institutional clinical trial treating oral cavity and oropharyngeal SCC patients with the mTOR inhibitor rapamycin, which achieved encouraging results in terms of objective responses and limited toxicities (Day et al. 2019). Thus, the frequent activation of the PI3K/mTOR pathway in SCC and its cancer-driving role may represent a vulnerability that can be targeted therapeutically. This pathway dependence is also being investigated clinically in multiple trials using direct PI3K and/or mTOR inhibitors in oral cavity and oropharyngeal SCC, as well as by the use of metformin, which blocks mTOR indirectly, for oral cavity SCC prevention in patients with potential premalignant lesions (Madera et al. 2015) (NCT02581137).

SCC in the New Era of Precision Immunotherapies

In addition to the molecular targeted options, there has been a recent revolution in cancer therapy, based on the ability to reactivate the antitumor response of the patient’s own immune system. In particular for oral cavity and oropharyngeal SCC, these cancers deploy multiple mechanisms to avoid immune recognition and subsequent antitumor immune response. This includes the recruitment of myeloid-derived suppressor cells and conditioning of the surrounding microenvironment to become highly immune suppressive by expressing cytokines, such as interleukin-6, interleukin-10, and transforming growth factor β, leading to the accumulation of suppressive regulatory T cells (Tregs) and the polarization of macrophages toward an immune-suppressive (M2) tumor-associated macrophage phenotype (Ferris 2015). A key emerging mechanism of tumor immunosuppression involves T-cell exhaustion. In many cancers, the antitumor T-cell reactivity is impaired due to activation of T-cell checkpoints, including PD-1, by its ligand, PD-L1, which is expressed by macrophages and some cancer cells, including SCC, which limit T-cell activation (Lyford-Pike et al. 2013). New immunotherapeutic agents, such as pembrolizumab and nivolumab (that inhibit PD-1), have recently demonstrated potent antitumor activity in a subset of oral cavity and oropharyngeal SCC patients (Chow et al. 2016; Ferris et al. 2016). These novel anti–PD-1 T-cell targeted therapeutics can reactivate antitumor T-cell responses, leading to improved survival with respect to standard therapies in 13% to 20% of head and neck cancer patients, often leading to durable responses (Chow et al. 2016; Ferris et al. 2016). However, the patients who will respond is unknown, and there is an urgent need to identify clinically validated biomarkers predicting the clinical activity of anti–PD-1 immunotherapies and novel therapeutic options for the >80% of patients who do not respond to anti–PD-1 treatment as a single agent. Ultimately, it can be expected that in only a few years, the full potential of precision immune oncology may be realized by targeting molecular alterations driving the progression of SCC lesions based on their individual oncogenomic landscape, combined with new immunotherapeutic options to restore the patient’s own anticancer immunity.

Conclusion

Oral cavity cancers comprise almost half of all head and neck cancers. Over 90% of these cancers are squamous cell carcinomas, which have a poor 5-y survival rate. Accurate diagnostic criteria are important for treatment selection. Integration of mechanistic studies with clinical findings could enhance diagnosis and treatment of SCC and provide information about novel therapeutic targets. In parallel, the recent revolution in cancer immunotherapy has provided new challenges and opportunities. Mechanistic biomarkers predicting a favorable response to anti–PD-1 treatment need to be identified, and the emerging knowledge of immune-suppressive mechanisms in head and neck cancers may afford the opportunity to develop new immunotherapeutic strategies to achieve durable remission (cure) of SCC lesions arising in the oral cavity and oropharynx.

Author Contributions

N.J. D’Silva, J.S. Gutkind, contributed to conception and design, drafted and critically revised the manuscript. Both authors gave final approval and agree to be accountable for all aspects of the work.

Acknowledgments

The authors thank Dr. Ligia Schmitd for help with the illustration.

Footnotes

This work was supported by grants from the National Institutes of Health / National Institute of Dental and Craniofacial Research DE027551 (N.J. D’Silva) and DE026644 and DE026870 (J.S. Gutkind).

J.S. Gutkind is a consultant for Oncoceutics, Vividion, and Domain and receives research support from Kura Oncology and Celldex Therapeutics. The authors declare no other potential conflicts of interest with respect to the authorship and/or publication of this article.

References

  1. Ang KK. 2008. Multidisciplinary management of locally advanced SCCHN: optimizing treatment outcomes. Oncologist. 13(8):899–910. [DOI] [PubMed] [Google Scholar]
  2. Ang KK, Zhang Q, Rosenthal DI, Nguyen-Tan PF, Sherman EJ, Weber RS, Galvin JM, Bonner JA, Harris J, El-Naggar AK, et al. 2014. Randomized phase III trial of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III to IV head and neck carcinoma: RTOG 0522. J Clin Oncol. 32(27):2940–2950. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Ayala GE, Dai H, Powell M, Li R, Ding Y, Wheeler TM, Shine D, Kadmon D, Thompson T, Miles BJ, et al. 2008. Cancer-related axonogenesis and neurogenesis in prostate cancer. Clin Cancer Res. 14(23):7593–7603. [DOI] [PubMed] [Google Scholar]
  4. Batsakis JG. 1985. Nerves and neurotropic carcinomas. Ann Otol Rhinol Laryngol. 94(4 Pt 1):426–427. [PubMed] [Google Scholar]
  5. Bernier J, Cooper JS, Pajak TF, van Glabbeke M, Bourhis J, Forastiere A, Ozsahin EM, Jacobs JR, Jassem J, Ang KK, et al. 2005. Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501). Head Neck. 27(10):843–850. [DOI] [PubMed] [Google Scholar]
  6. Binmadi NO, Basile JR. 2011. Perineural invasion in oral squamous cell carcinoma: a discussion of significance and review of the literature. Oral Oncol. 47(11):1005–1010. [DOI] [PubMed] [Google Scholar]
  7. Bonner JA, Harari PM, Giralt J, Cohen RB, Jones CU, Sur RK, Raben D, Baselga J, Spencer SA, Zhu J, et al. 2010. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol. 11(1):21–28. [DOI] [PubMed] [Google Scholar]
  8. Brandwein-Gensler M, Smith RV, Wang B, Penner C, Theilken A, Broughel D, Schiff B, Owen RP, Smith J, Sarta C. 2010. Validation of the histologic risk model in a new cohort of patients with head and neck squamous cell carcinoma. Am J Surg Pathol. 34(5):676–688. [DOI] [PubMed] [Google Scholar]
  9. Cancer Genome Atlas Network. 2015. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature. 517(7536):576–582. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Chi AC, Katabi N, Chen HS, Cheng YL. 2016. Interobserver variation among pathologists in evaluating perineural invasion for oral squamous cell carcinoma. Head Neck Pathol. 10(4):451–464. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Chinn SB, Spector ME, Bellile EL, McHugh JB, Gernon TJ, Bradford CR, Wolf GT, Eisbruch A, Chepeha DB. 2013. Impact of perineural invasion in the pathologically N0 neck in oral cavity squamous cell carcinoma. Otolaryngol Head Neck Surg. 149(6):893–899. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Chow LQM, Haddad R, Gupta S, Mahipal A, Mehra R, Tahara M, Berger R, Eder JP, Burtness B, Lee SH, et al. 2016. Antitumor activity of pembrolizumab in biomarker-unselected patients with recurrent and/or metastatic head and neck squamous cell carcinoma: results from the phase Ib keynote-012 expansion cohort. J Clin Oncol. 34(32):3838–3845. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Chung CH, Ely K, McGavran L, Varella-Garcia M, Parker J, Parker N, Jarrett C, Carter J, Murphy BA, Netterville J, et al. 2006. Increased epidermal growth factor receptor gene copy number is associated with poor prognosis in head and neck squamous cell carcinomas. J Clin Oncol. 24(25):4170–4176. [DOI] [PubMed] [Google Scholar]
  14. Cruveilhier J. 1835. Maladies des nerfs. Paris: J. B. Bailliere. [Google Scholar]
  15. Czerninski R, Amornphimoltham P, Patel V, Molinolo AA, Gutkind JS. 2009. Targeting mammalian target of rapamycin by rapamycin prevents tumor progression in an oral-specific chemical carcinogenesis model. Cancer Prev Res (Phila). 2(1):27–36. [DOI] [PubMed] [Google Scholar]
  16. Day TA, Shirai K, O’Brien PE, Matheus MG, Godwin K, Sood AJ, Kompelli A, Vick JA, Martin D, Vitale-Cross L, et al. 2019. Inhibition of mTOR signaling and clinical activity of rapamycin in head and neck cancer in a window of opportunity trial. Clin Cancer Res. 25(4):1156–1164. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. El-Deiry WS, Goldberg RM, Lenz HJ, Shields AF, Gibney GT, Tan AR, Brown J, Eisenberg B, Heath EI, Phuphanich S, et al. 2019. The current state of molecular testing in the treatment of patients with solid tumors, 2019. CA Cancer J Clin. 69(4):305–343. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Ettinger KS, Ganry L, Fernandes RP. 2019. Oral cavity cancer. Oral Maxillofac Surg Clin North Am. 31(1):13–29. [DOI] [PubMed] [Google Scholar]
  19. Ferlay J, Colombet M, Soerjomataram I, Mathers C, Parkin DM, Pineros M, Znaor A, Bray F. 2019. Estimating the global cancer incidence and mortality in 2018: Globocan sources and methods. Int J Cancer. 144(8):1941–1953. [DOI] [PubMed] [Google Scholar]
  20. Ferris RL. 2015. Immunology and immunotherapy of head and neck cancer. J Clin Oncol. 33(29):3293–3304. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Ferris RL, Blumenschein G, Jr, Fayette J, Guigay J, Colevas AD, Licitra L, Harrington K, Kasper S, Vokes EE, Even C, et al. 2016. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. 375(19):1856–1867. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Hoadley KA, Yau C, Hinoue T, Wolf DM, Lazar AJ, Drill E, Shen R, Taylor AM, Cherniack AD, Thorsson V, et al. 2018. Cell-of-origin patterns dominate the molecular classification of 10,000 tumors from 33 types of cancer. Cell. 173(2):291–304e6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Jerjes W, Upile T, Hamdoon Z, Mosse CA, Akram S, Hopper C. 2011. Prospective evaluation of outcome after transoral CO2 laser resection of T1/T2 oral squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 112(2):180–187. [DOI] [PubMed] [Google Scholar]
  24. Leemans CR, Snijders PJF, Brakenhoff RH. 2018. The molecular landscape of head and neck cancer. Nat Rev Cancer. 18(5):269–282. [DOI] [PubMed] [Google Scholar]
  25. Liebig C, Ayala G, Wilks JA, Berger DH, Albo D. 2009. Perineural invasion in cancer: a review of the literature. Cancer. 115(15):3379–3391. [DOI] [PubMed] [Google Scholar]
  26. Lin C, Cao W, Ren Z, Tang Y, Zhang C, Yang R, Chen Y, Liu Z, Peng C, Wang L, et al. 2017. GDNF secreted by nerves enhances PD-L1 expression via JAK2-STAT1 signaling activation in HNSCC. Oncoimmunology. 6(11):e1353860. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Lyford-Pike S, Peng S, Young GD, Taube JM, Westra WH, Akpeng B, Bruno TC, Richmon JD, Wang H, Bishop JA, et al. 2013. Evidence for a role of the PD-1:PD-L1 pathway in immune resistance of HPV-associated head and neck squamous cell carcinoma. Cancer Res. 73(6):1733–1741. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Madera D, Vitale-Cross L, Martin D, Schneider A, Molinolo AA, Gangane N, Carey TE, McHugh JB, Komarck CM, Walline HM, et al. 2015. Prevention of tumor growth driven by PIK3CA and HPV oncogenes by targeting mTOR signaling with metformin in oral squamous carcinomas expressing OCT3. Cancer Prev Res. 8(3):197–207. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Mendenhall WM, Amdur RJ, Palta JR. 2006. Intensity-modulated radiotherapy in the standard management of head and neck cancer: promises and pitfalls. J Clin Oncol. 24(17):2618–2623. [DOI] [PubMed] [Google Scholar]
  30. Molinolo AA, Hewitt SM, Amornphimoltham P, Keelawat S, Rangdaeng S, Meneses Garcia A, Raimondi AR, Jufe R, Itoiz M, Gao Y, et al. 2007. Dissecting the AKT/mammalian target of rapamycin signaling network: emerging results from the head and neck cancer tissue array initiative. Clin Cancer Res. 13(17):4964–4973. [DOI] [PubMed] [Google Scholar]
  31. Molinolo AA, Marsh C, El Dinali M, Gangane N, Jennison K, Hewitt S, Patel V, Seiwert TY, Gutkind JS. 2012. mTOR as a molecular target in HPV-associated oral and cervical squamous carcinomas. Clin Cancer Res. 18(9):2558–2568. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Roberts TJ, Colevas AD, Hara W, Holsinger FC, Oakley-Girvan I, Divi V. 2016. Number of positive nodes is superior to the lymph node ratio and American Joint Committee on Cancer N staging for the prognosis of surgically treated head and neck squamous cell carcinomas. Cancer. 122(9):1388–1397. [DOI] [PubMed] [Google Scholar]
  33. Safi AF, Grandoch A, Nickenig HJ, Zoller JE, Kreppel M. 2017. Importance of lymph node ratio for locoregional recurrence of squamous cell carcinoma of the buccal mucosa. Head Neck. 39(12):2488–2493. [DOI] [PubMed] [Google Scholar]
  34. Scanlon CS, Banerjee R, Inglehart RC, Liu M, Russo N, Hariharan A, van Tubergen EA, Corson SL, Asangani IA, Mistretta CM, et al. 2015. Galanin modulates the neural niche to favour perineural invasion in head and neck cancer. Nat Commun. 6:6885. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Schmitd LB, Beesley LJ, Russo N, Bellile EL, Inglehart RC, Liu M, Romanowicz G, Wolf GT, Taylor JMG, D’Silva NJ. 2018. Redefining perineural invasion: integration of biology with clinical outcome. Neoplasia. 20(7):657–667. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Schmitd LB, Scanlon CS, D’Silva NJ. 2018. Perineural invasion in head and neck cancer. J Dent Res. 97(7):742–750. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Sessions DG, Spector GJ, Lenox J, Haughey B, Chao C, Marks J. 2002. Analysis of treatment results for oral tongue cancer. Laryngoscope. 112(4):616–625. [DOI] [PubMed] [Google Scholar]
  38. Shen WR, Wang YP, Chang JY, Yu SY, Chen HM, Chiang CP. 2014. Perineural invasion and expression of nerve growth factor can predict the progression and prognosis of oral tongue squamous cell carcinoma. J Oral Pathol Med. 43(4):258–264. [DOI] [PubMed] [Google Scholar]
  39. Siegel RL, Miller KD, Jemal A. 2019. Cancer statistics, 2019. CA Cancer J Clin. 69(1):7–34. [DOI] [PubMed] [Google Scholar]
  40. Sparano A, Weinstein G, Chalian A, Yodul M, Weber R. 2004. Multivariate predictors of occult neck metastasis in early oral tongue cancer. Otolaryngol Head Neck Surg. 131(4):472–476. [DOI] [PubMed] [Google Scholar]
  41. Tai SK, Li WY, Yang MH, Chang SY, Chu PY, Tsai TL, Wang YF, Chang PM. 2012. Treatment for T1-2 oral squamous cell carcinoma with or without perineural invasion: neck dissection and postoperative adjuvant therapy. Ann Surg Oncol. 19(6):1995–2002. [DOI] [PubMed] [Google Scholar]
  42. Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, Erfan J, Zabolotnyy D, Kienzer HR, Cupissol D, et al. 2008. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 359(11):1116–1127. [DOI] [PubMed] [Google Scholar]

Articles from Advances in Dental Research are provided here courtesy of International and American Associations for Dental Research

RESOURCES