Field cancerisation is a concept introduced by Slaughter et al [1]. It refers to the process in which the cancerous part is not limited to a definable area of tissue. Cancerisation happens over wide areas of mucosa that are not visible to the naked eye and cannot be identified through traditional histological methods. However, genetically identifiable Pro tumorigenic mutant clones can be detected. Field cancerisation is also known as the field effect, lateral cancerisation or condemned mucosa. It is a well-established concept, but currently there is no effective management protocol available. Field cancerisation has been observed in extra-oral sites such as the gastrointestinal tract, lungs, skin, cervix, colon and breast [2].In the case of lung cancer patients who smoke, the effects of field cancerisation can be seen in the oral cavity [3]. Field cancerisation is often responsible for the development of synchronous or metachronous lesions and a few recurrent oral carcinomas. Currently, extensive molecular-level research is being conducted worldwide to understand the molecular pathogenesis of field cancerisation for targeted prevention and therapeutic applications. This article provides a narrative review of the management techniques available for field cancerisation of the oral cavity.

Sequence of Field Changes in Oral Mucosa

When an area of the mucosa is repeatedly exposed to carcinogens, it can develop into a visible carcinomatous lesion. The adjacent area may show signs of premalignancy, but genetic changes occur throughout the mucosal field exposed to the carcinogenic agent, spanning up to 7 cm [4]. These genetic changes are not visible on microscopic examination but can be appreciated on a molecular level study and are referred to as the field effect. This effect is not limited to the epithelium, as stroma can also show field changes [5]. Over time, genetic changes lead to dysplastic changes in the mucosa, which can develop into clinically visible premalignant lesions that can transform into carcinoma. Since these field changes are multifocal, they can lead to malignant outbreaks at different intervals, which are referred to as second primaries or local recurrence based on Warren and Gates criteria [6]. This phenomenon is a result of field cancerization.

Significance of Field Cancerisation

Management of oral cancer mainly involves wide excision of the cancerous part with safe margins. A clinical safe margin differs from a histological safe margin. The goal is to achieve a safe histological margin of a minimum of 5mm. However, there can be field effect in histologically normal appearing oral mucosa making the concept of safe margin unreliable. The incidence of second primary cancer of the oral cavity according to Rogers et al is 1.7 % within two years, 4.9% within five years, and 7.8% within ten years [7]. In a retrospective analysis conducted by González-García, R et al 5.6% of the oral cancer cases developed second primary tumours and 19% of the cases developed local recurrence during the follow-up period of 52.27 + 49.52 months. Among the patients who developed local recurrence 16.2% had surgical margins greater than 1 cm. Among the patients who developed second primary tumours 5.8% had surgical margins greater than 1 cm [8]. The reason behind the incidence of second primary tumours and local recurrence is the presence of condemned mucosa by carcinogenic agents like tobacco and alcohol. Even though well treated with proper surgical technique and clear histological margins, these outcomes of field cancerisation increase the morbidity of an individual sometimes leading to mortality,increasing the health care burden to the institution and thus the nation. Hence, effective management of field cancerisation is of utmost importance to prevent post-treatment failures because of synchronous or metachronous lesions.

Oral Cavity Screening

It is extremely important to meticulously examine the entire oral cavity before starting treatment for oral cancer. Apart from the cancerous tissue, the remaining oral cavity may have pre-malignant changes, such as submucous fibrosis, leukoplakia, smoker's palate or tobacco keratosis, which could turn into cancer later due to field effect. Therefore, it is recommended to thoroughly investigate these lesions to rule out malignancy and provide appropriate management. Patients with these changes may benefit from habit counselling sessions and preventive strategies. Fluorescence-based tools can be used to assist in the early detection of cancer. They can help identify areas at risk, sites to be biopsied and redefine surgical margins intraoperatively [9].

Habit Cessation Counselling

Continuous exposure to carcinogens in areas that have undergone field changes can eventually lead to carcinomatous transformation,depending on the severity of genetic mutations. As such, it is recommended that habit cessation counseling be included in the treatment plan from the very first day and reinforced during each visit. A recent systematic review conducted by Patricia R et al concluded that quitting smoking in cases of head and neck cancer has been shown to improve overall survival rates, reduce the likelihood of recurrence, and decrease the chances of developing secondary tumors [10].

Nutritional Supplements (Nutraceuticals)

Nutraceuticals are compounds derived from food sources that have preventive and therapeutic properties towards diseases [11]. The role of phytochemicals and antioxidants in preventing certain types of human cancers has been studied for decades [12]. Bioactive dietary components, including epigenetic, antioxidant, anti-inflammatory, and anti-angiogenic functions, help in preventing oral cancer, reversing premalignant changes, and reducing the incidence of secondary lesions. This is often referred to as green chemoprevention. Some of the oncopreventive compounds in oral cancer include Epigallocatechin gallate from green tea, Resveratrol, Curcumin, lycopene, antioxidant vitamins and minerals such as vitamins A, E, C, selenium, and zinc, and vegetables and fruits that contain high levels of micronutrients [13].

Chemoprevention

Chemotherapy is one of the treatment options for oral cancer. Preventive chemotherapy can be used to interrupt the malignant transformation of premalignant changes in the oral cavity like submucous fibrosis and leukoplakia. Chemoprevention of field cancerisation is also an option that is mentioned in literature. The cancer stem cell model suggests that the formation of cancer stem cells, either from the transformation of normal cells or the de-differentiation of tumor cells, leads to the development of cancer. These cancer stem cells eventually develop into cancer in a stepwise manner Anti-cancer stem cell therapy, gene therapy, or targeted therapy can use drugs to alter or reverse molecular changes in the field containing cancer stem cells. Clinical trials have been conducted on 13-cis retinoic acid, Cyclo-Oxygenase-2(COX-2) inhibitors and epidermal growth factor receptor (EGFR) inhibitors to assess their efficacy in preventing the development of cancer from pre-malignant lesions. Histology-based examinations were done to see their effect at the cellular level.

4A) Retinoids: 13-cis-retinoic acid is known to promote cellular differentiation, halt proliferation and regulate tumour suppressor genes, which ultimately results in the inhibition of tumour growth. Although preclinical studies have shown positive results for retinoids, head and neck clinical trials have not been promising in using retinoids as preventive drugs for second primaries or inhibiting tumour recurrence. Low-dose retinoic acid is not effective in preventing second primaries [14]. However, high-dose retinoic acid has shown significant results in preventing second primary tumours, as demonstrated by Hong et al [15]. Nonetheless, confirmatory statements are still pending as large-scale clinical trials are awaited.

4B) COX 2 Inhibitors:The use of COX 2 inhibitors as a chemo-preventive agent is based on the idea that these inhibitors can block the synthesis of prostaglandins, which are known to promote tumorigenic effects such as cell proliferation and angiogenesis. Celecoxib is an example of a COX 2 inhibitor. Although in vitro and animal studies support their use in preventing the development of cancerous cells from premalignant lesions, there is still a lack of strong scientific evidence from in vivo studies [16]. Moreover, side effects associated with these chemo-preventive agents and the possibility of relapse following cessation of therapy should also be taken into account before deciding to use them [17].

4C) Targeted Immunotherapy - Targeted therapy involves the use of drugs that target the cancer-initiating cell signalling pathways and thus have high selectivity and less toxicity compared to previous drugs [18]. EGFR inhibitors like cetuximab and Erlotinibe, Programmed Cell Death Receptor 1 targeting drugs like Pembrolizumab; and Vascular endothelial growth factor inhibitors like bevacizumab are used in oral cancer management as a combination chemotherapy in advanced oral cancer cases along with standard chemo drugs. But they don’t have a proven efficacy in the prevention of oral cancer and management of field cancerisation. Gene therapy using oncolytic genetically engineered viruses to affect the genetic material of tumour cells is still limited to the initial phase of human trials and long-term studies are yet to be initiated to know the precise role of these drugs in the management of field cancerisation [19].

Cytokine therapy using Interferon - alpha, interleukins and salivary cytokines; Adoptive cellular immunotherapy using lymphokine-activated killer (LAK) cells, chimeric antigen receptor T (CAR-T) cells, CD3AcAb-activated killer (CD3AK) cells, cytokine-induced killer (CIK) cells, and Dendritic cells are in initial phases of clinical trials. They help to deliver anti-tumour immunity or strengthen the natural immunity against cancer-driving cells [20].Sound knowledge of tumour biology which varies with every patient helps in the precise delivery of immunotherapy.

4D) Cancer vaccines: Oral cancer vaccines, including peptide-based, human papillomavirus, and immunotherapy-based vaccines, have been introduced in the past decade [21]. However, there is a lack of data on their effectiveness and long-term studies.

Photodynamic Therapy (PDT)

Photodynamic therapy (PDT) is a type of treatment that involves the use of a photosensitizer which when applied to a specific area and exposed to a particular wavelength of light, it reacts with tissue oxygen, releasing reactive oxygen species. These cytotoxic species help to occlude the tumor vasculature and induce a systemic immune response against the tumor [22]. Commonly used photosensitizers for oral cavity cancers include 5-aminolevulinic acid, Methylene blue, Porphyrin, Foscan, and Chlorin e6.New-generation photosensitizers have been developed to overcome the disadvantages of PDT. They use nanoparticles that can penetrate deeper into the tissue than conventional photosensitizers and are less toxic to adjacent normal mucosa. These new photosensitizers are more specific to cancer cells.

 PDT has been found to be effective in cases of field cancerization, potentially malignant disorders, carcinoma in-situ, T1 and T2 stage lesions of the oral cavity and larynx, second primaries or recurrences in case of operated carcinomas of the oral cavity. According to a few reviews on the effect of PDT on various oral precancerous and cancerous lesions, complete response and recurrence after photodynamic therapy ranges from 32.9% - 92% and 7% - 26.5%, respectively [23]. According to Shailesh et al, complete, partial, and no response to PDT was found in 22.58% - 100%, 4% - 66%, and 0% - 38.70% of Potentially Malignant Disorders, respectively, and 16% - 100% of complete response in Head and neck malignancy patients [24]. Doeveren et al conducted a retrospective analysis on the role of Adjuvant PDT in the case of close and positive resection margins in Head and neck carcinomas. The 2-year progression-free survival rate was 30%; the 2-year disease-free survival rate was 28%; and the 2-year overall survival was 51%. They proposed a minimum time interval of 6 weeks between surgery and photodynamic therapy for better disease-free survival [25]. PDT can be a great tool for managing field cancerization because it is effective over the superficial layers of the oral mucosa. It can be used over large areas with no grave adverse effects and can be repeated .It can even be employed during the premalignant stage to prevent cancerous transformation or after surgery or radiotherapy to prevent recurrences and second primaries.

Boron Neutron Capture Therapy (BNCT)

Boron Neutron Capture Therapy (BNCT) is a type of particle radiotherapy that uses Boron-10 compounds like Boronophenylalanine (BPA) and Borocaptate sodium (BSH) to target cancer cells. These compounds are selectively absorbed by tumour cells and when exposed to a neutron beam, they release alpha particles and helium nuclei. This results in the death of cancerous cells by inhibiting DNA synthesis through a process called "linear energy transfer" [26]. BNCT provides biochemical targeting of tissues, making it more selective towards tumour tissue instead of adjacent normal tissue. The Hamster cheek pouch model and mouse oral Squamous Cell Carcinoma xenograft model explain the effect of BNCT in oral cancer. Studies have shown that BNCT has a therapeutic effect on Precancerised Oral Mucosa in the hamster cheek pouch model by delaying the development of second primary tumours and inhibiting DNA synthesis [27]. However, there are no long-term prospective human studies available to determine the accurate action of BNCT in the management of field cancerisation. Additionally, BNCT requires a nuclear reactor setup which is currently unavailable in most nations.

Excision of Premalignant Lesions

It is a lesion-directed approach to manage field cancerisation in which the individual will be kept under strict follow-up and any lesion that shows signs of premalignancy will be excised and histopathologically and molecular level examination to be done during the initial stages to rule out dysplasia or identify carcinoma in its early stage. This is mainly indicated in the case of individuals with widespread oral potentially malignant disorders like submucous fibrosis, leukoplakia, and oral epithelial dysplasia. A smaller threshold to perform a biopsy to be followed in case of an oral ulcer or a sudden change in the clinical appearance of a long-standing lesion in an individual with concomitant conditions having high malignant transformation potential like oral submucous fibrosis, proliferative leukoplakia, erythroplakia and even in post-surgery cases. This helps in early identification and appropriate management of the concerned lesion.

Mirror Image Biopsies

Mirror image biopsy is a diagnostic technique used to identify any signs of pre-malignancy in the contralateral clinically normal-looking oral mucosa of an individual with unilateral carcinoma of the oral cavity. The technique involves a thorough histological, immunohistochemical and molecular examination of the biopsied tissue to assist in immediate management options for field cancerisation during the primary tumour's management and recommend a vigilant follow-up schedule. Several recent studies have highlighted the critical role of mirror image biopsies in early identification of oral field cancerisation [28]. According to Peralta et al, 57.3% of clinically normal oral mucosa show histopathological changes [29]. Predictive immunohistochemical markers of field cancerisation include p53, Ki-67, and cytokeratins. Telomere shortening is an early marker for field cancerisation [30].

Management of oral cancer should not be just limited to treating the lesion area alone. Genetic changes happen throughout the mucosa making the individual susceptible to cancer in later dates even after successful management of the primary lesion because of filed cancerisation. Field cancerisation identification and management should be part of the treatment plan in every oral cancer individual to prevent recurrences, and secondary tumours, to formulate a proper follow-up schedule, to reduce health care burden, improve disease-free survival and even for medicolegal purposes. There is a dire need for research towards early identification of field cancerisation through non-invasive methods, molecular markers and effective management protocols to be proposed by conducting prospective long-term studies with high significance value. Effective management of field cancerisation helps in the prevention of oral cancer, termination of malignant transformation of altered mucosa and enhances the post-management survival of individuals affected with oral cancer.

1. Slaughter DP, Southwick HW, Smejkal W. Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin Cancer. 1953; 6: 5-963.
2. Graham TA, Mc Donald SA, Wright NA. Field cancerization in the GI tract. Future Oncol. 2011; 7: 981-993.
3. Sidransky D. The oral cavity as a molecular mirror of lung carcinogenesis. Cancer Prev Res. 2008, 1: 12-14.
4. Tabor MP, Brakenhoff RH, Ruijter-Schippers HJ, E van der Wal J. Snow GB, Leemans CR, et al. Multiple head and neck tumors frequently originate from a single preneoplastic lesion. Am J Pathol. 2002; 161: 1051-60.
5. Ge L, Meng W, Zhou H, Bhowmick N. Could stroma contribute to field cancerization? Med Hypotheses. 2010; 75: 26-31.
6. Warren S, Gates O. Multiple primary malignant tumors, a survey of the literature and a statistical study. Am J Cancer. 1932, 16: 1358-1414.
7. Rogers SN , Swain A, Carroll C, Lowe Incidence, timing, presentation, treatment, and outcomes of second primary head and neck squamous cell carcinoma after oral cancer. Br J Oral Maxillofac Surg. 2019; 57: 1074-80.
8. Gonzalez-Garcia R, Naval-Gias L, Roman-Romero L, Sastre-Perez J, Rodriguez-Campo F. Local recurrences and second primary tumors from squamous cell carcinoma of the oral cavity. A retrospective analytic study of 500 patients. Head & Neck. 2009; 31: 1168-80.
9. Nomura T, Shibahara T. Detection of field alterations using useful tools for oral squamous cell carcinoma. Jpn Dent Sci Rev. 2013; 49: 106-115.
10. R Von Kroge P, Bokemeyer F, Ghandili S, Bokemeyer C, Seidel C. The Impact of Smoking Cessation and Continuation on Recurrence and Survival in Patients with Head and Neck Cancer: A Systematic Review of the Literature. Oncol Res Treat. 2020; 43: 549-558.
11. Zlotogorski A, Dayan A, Dayan D, Chaushu G, Salo T, Vered M. Nutraceuticals as new treatment approaches for oral cancer: II. Green tea extracts and resveratrol. Oral Oncology. 2013; 49: 502-06.
12. Garewal H. Antioxidants in oral cancer prevention. Am J Clin Nutr. 1995; 62: 1410-16.
13. Rodriguez-Molinero J, Miguelanez-Medran BDC, Puente-Gutierrez C, Delgado-Somolinos E, Carreras-Presas CM, Fernandez-Farhall J, et al. Association between Oral Cancer and Diet: An Update. Nutrients. 2021; 15: 1299.
14. Aarti KB, Ju?whei L, Harlan AP, Charlotte DJ, Paul JL, Philip R, et al. Double-Blind, randomized phase 3 trial of low-dose 13-cis retinoic acid in the prevention of second primaries in head and neck cancer. Long-term follow-up of a trial of the eastern cooperative oncology group-ACRIN Cancer research group (C0590). Cancer. 2017; 123: 4653-62.
15. Hong WK, Lippman SM, Itri LM, Karp DD, Lee JS, Byers RM, et al. Prevention of second primary tumours with isotretinoin in squamous-cell carcinoma of the head and neck. New Engl J Med. 1990; 323: 795-801.
16. Papadimitrakopoulou VA, William WN, Lippman MS, Lee JJ, Ondrey FG, Peterson DE, et al. Pilot randomized phase II study of celecoxib in oral premalignant lesions. Clin Cancer Res. 2008; 14: 2095-2101.
17. Smith W, Saba N. Retinoids as chemoprevention for head and neck cancer: where do we go from here? Crit Rev Oncol Hematol. 2005; 55: 143-152.
18. Takahashi-Yanaga F, Kahn M. Targeting Wnt Signaling: Can We Safely Eradicate Cancer Stem Cells? Clin Cancer Res. 2010; 12: 3153-62.
19. Shilpa P, Kaul R, Bhat S, Sultana N, Pandeshwar P. Oncolytic viruses in head and neck cancer: a new ray of hope in the management protocol. Ann Med Health Sci Res. 2014; 3: 178.
20. Liu C, Wang M, Zhang H, Li C, Zhang T, Liu H, et al. Tumor microenvironment and immunotherapy of oral cancer. Eur J Med Res. 2022; 27.
21. Nielsen KJ, Jakobsen KK, Jensen JS, Gronhoj C, Von Buchwald C. The Effect of Prophylactic HPV Vaccines on oral and oropharyngeal HPV Infection-A Systematic Review. Viruses. 2021; 13: 1339-2021.
22. Duzgune? N, Piskorz J, Skupin-Mrugalska P, Goslinski T, Mielcarek J, Konopka Photodynamic therapy of oral cancer and novel liposomal photosensitizers. Oral. 2023; 3: 276-294.
23. Jeroen M, Pierre D, Poorten V, Vincenta. Photodynamic therapy in head and neck cancer: indications, outcomes, and future prospects. Current Opinion in Otolaryngology & Head and Neck Surgery. 2019; 2: 136-141.
24. Gondivkar SM, Gadbail AR, Choudhary MG, Vedpathak PR, Likhitkar MS. Photodynamic treatment outcomes of potentially-malignant lesions and malignancies of the head and neck region: A systematic review. J Investig Clin Dent. 2018, 9.
25. van Doeveren TEM, Karakullukcu MB, van Veen RLP, Lopez-Yurda M, Schreuder WH, Tan BI. Adjuvant photodynamic therapy in head and neck cancer after tumor-positive resection margins. Laryngoscope. 2018; 128: 657-663.
26. Yura Y, Fujita Y. Boron neutron capture therapy as a novel modality of radiotherapy for oral cancer. Principle and antitumor effect. Oral Science International. 2013; 10: 9-14.
27. Heber EM, Aromando RF, Trivillin VA, Itoiz ME, Nigg DW, Kreimann EL. et al. Therapeutic effect of boron neutron capture therapy (BNCT) on field cancerized tissue. inhibition of DNA synthesis and lag in the development of second primary tumors in precancerous tissue around treated tumors in DMBA-induced carcinogenesis in the hamster cheek pouch oral cancer model. Arch Oral Biol. 2007; 52: 273-279.
28. Gupta V, Ramani P. Histologic and immunohistochemical evaluation of mirror image biopsies in oral squamous cell carcinoma. J Oral Biol Craniofac Res. 2016; 6: 194-197.
29. Peralta-Mamani M, Terrero-Perez A, Tucunduva RMA, Rubira CMF, da Silva Santos PS, Honorio HM, et al. Occurrence of field cancerization in clinically normal oral mucosa: A systematic review and meta-analysis. Arch Oral Biol. 2022; 143.
30. Boscolo-Rizzo P, Da Mosto MC, Rampazzo E, Giunco S, Del Mistro A, Menegaldo A, et al.. Telomeres and telomerase in head and neck squamous cell carcinoma: from pathogenesis to clinical implications. Cancer Metastasis Rev. 2016; 35: 457-74.