|Year : 2015 | Volume
| Issue : 1 | Page : 35-40
Field effect in oral cancer: An update
Arunachalam Meyyappan, Ramya Malini, Raghavendra Karthik, Priyadarshini Natarajan, K Raj Kumar
Department of Oral Pathology, SRM Dental College, Ramapur am, Chennai, Tamil Nadu, India
|Date of Web Publication||19-Jan-2015|
Department of Oral Pathology, SRM Dental College, Ramapuram, Chennai - 600 089, Tamil Nadu
The concept of oral field cancerization (OFC) was first introduced by Slaughter et al. in 1953 in the setting of oral cancer, to propose the field cancerization theory which claims that after repeated exposure, the mucosa accumulates genetic alterations, resulting in the induction of multiple, independent, malignant lesions, thus field cancerization involves the lateral spread of premalignant or malignant disease and contributes to the recurrence of head and neck tumors. The molecular studies regarding OFC have been expanding exponentially since a few years. The need for chemoprevention and the management of OFC with its resultant effects of development of second primary tumors (SPTs) have been challenging till today. Hence, the article tries to explain the conflicting aspects of various mechanisms by which SPTs develop, the molecular techniques and chemoprevention of OFC.
Keywords: Field cancerization, oral cancer, second primary tumor
|How to cite this article:|
Meyyappan A, Malini R, Karthik R, Natarajan P, Kumar K R. Field effect in oral cancer: An update. SRM J Res Dent Sci 2015;6:35-40
|How to cite this URL:|
Meyyappan A, Malini R, Karthik R, Natarajan P, Kumar K R. Field effect in oral cancer: An update. SRM J Res Dent Sci [serial online] 2015 [cited 2020 Aug 13];6:35-40. Available from: http://www.srmjrds.in/text.asp?2015/6/1/35/149589
| Introduction|| |
Oral cancer is a significant public health threat accounting for 270,000 new cases annually worldwide.  In general, one-third of head and neck squamous cell carcinoma (HNSCC) patients present with early-stage (I and II) disease, whereas the remaining have advanced disease (stages III and IV) at presentation. 
Oral squamous cell carcinoma (OSCC) is the most common malignancy of the oral cavity that arises in the mucosal linings. Survival rate of OSCC patients depends mainly on tumor size, nodal involvement development of new tumor or recurrence of an incompletely resected primary tumor.
The prognosis of HNSCC patients is adversely influenced by the development of second primary tumors (SPTs). Approximately, 2-3% of oral cancer patients develop a SPTs each year after removal of the primary tumor and 90% of recurrences manifest within 2 years of initial treatment. 
| Clinical definition of locally recurrent cancer|| |
After surgical removal of an HNSCC, patients have a considerable risk of developing cancer at same place or near to that place.
To differentiate between local recurrence and an SPT, local recurrence is defined, according to clinical criteria, cancer that develops from same place of the primary tumor or occurring at a distance <2 cm from the initial tumor and within 3 years after the primary tumor. 
| Clinical definition of second primary tumors|| |
Besides the clinical problems related to the index tumor, HNSCC patients are at high risk for developing SPTs.
The criteria for classifying a tumor as a second primary malignancy have remained consistent since they were first proposed in 1932 by Warren and Gates:
- Histologic confirmation of malignancy in both the index and secondary tumors.
- There should be at least 2 cm of normal mucosa between the tumors. If the tumors are in the same location, then they should be separated in time by at least 5 years. 
To exclude the possibility of a local recurrence, most studies use a distance of at least 2 cm between the first tumor and the SPT. 
According to Cunliffe et al.  SPTs can be divided into two groups:
Synchronous SPTs, which develop simultaneously with or within 6 months after the index tumor, they should not consist of submucosal spread or a satellite lesion of each other. In any other case they are considered as regional spread or metastatic lesions and metachronous SPTs, which develop >6 months after the initial tumor,. The term SPT suggests that these tumors and the index tumors have developed independently.
Recently, however, genetic studies done by Bedi et al. have shown that, in the proportion of cases, the first and second tumors have originated from the same precursor cell.
In their classical paper of 1953, Slaughter et al.,  used the term field cancerization for the first time, when studying oral cancer.
Field cancerization or the "field effect" was and is used in the context of the existence of (pre-) neoplastic processes at multiple sites, often with the unproven assumption that these have developed independently. 
The investigators examined pathology slides from 783 patients with head and neck cancer in an effort to understand the gross changes found in epithelia surrounding these tumors and explain their clinical behavior. It was discovered that all of the epithelium beyond the boundaries of tumor possessed histologic changes, and 88/783 of patients were found to have more than one independent area of malignancy. 
On the basis of recent molecular findings field cancerization is defined as the "the presence of one or more areas consisting of epithelial cells that have genetic alterations. A field lesion (or shortly "field") has a monoclonal origin and does not show invasive growth and metastatic behavior, the hallmark criteria of cancer." 
Genetical dimension of field cancerization
Molecular basis for cancer development has been addressed by several studies and genetic progression models have been proposed for various tumor types. It is now well established that genetic alterations forms the basis for the progression from a normal cell to a cancer cell, referred to as the process of multistep carcinogenesis. 
Three theories have been proposed to explain the occurrence of the multiple tumors:
- Monoclonal theory where multiple genetically related tumors arise from a single cell through mucosal spread.
- Polyclonal theory in which multiple transforming events give rise to genetically unrelated multiple tumors.
- Multiple lesion arise due to the widespread migration of transformed cells through the whole aerodigestive tract. Migration of tumor cells can occur through saliva by micrometastases or through intraepithelial migration of the progeny of the initially transformed cells. ,
| Oral field changes and their relationship with risk factors|| |
In 1962, Nieburgs et al.  Reported malignancy-associated changes within smear cells of normal buccal mucosa in patients with malignant disease. The changes consisted of an increase in nuclear size, discontinuous nuclear membrane, numerous Feulgen-negative areas, increased associated chromatin surrounding the clear areas, and the absence of a single large nucleolus.
Incze et al.  Confirmed the increase in the nuclear area in normal oral mucosa remote from HNSCCs using ultrastructural analysis. They also described an altered nuclear to cytoplasmic area ratio.
Alterations in cytokeratin expression
Aberrant expression of cytokeratins has been shown during the process of HNSCC carcinogenesis. ,
Presence of cytokeratins 7, 8, 13, 16, and 19 was observed at abnormal anatomical sites or at abnormal intraepithelial levels in normal mucosa from HNSCC patients. ,,,
Changes in blood group antigens of the ABH system
In a study by Bongers et al.,  a 4-fold lower expression of type 2 chain ABH antigen was shown in exfoliated cells from macroscopically normal mucosa from six different places distant from HNSCC compared with healthy individuals, which they believed could be a promising negative marker for field change.
Foci of cyclin D1 expression
Increased cyclin D1 has also been demonstrated recently in cytosmears from healthy buccal mucosa which correlated with the extent of tobacco consumption. 
Izzo et al. observed strong evidence for early dysregulation of cyclin D1 expression during the tumorigenesis process and suggest that dysregulated increased expression precedes and possibly enables gene amplification. 
Bartkova et al.  Observed clearly defined foci of cyclin D1 expression in sections of normal mucosa adjacent to HNSCC that were not seen in sections of normal mucosa from healthy individuals. Thus, cyclin D1 amplification has been shown in premalignant lesions and the amplification frequency progresses from premalignant lesions to invasive carcinoma.
Increased expression of the epidermal growth factor receptor
Autophosphorylation occurs due to binding of ligand to the extracellular domain of epidermal growth factor receptor (EGFR) results in receptor dimerization which activates tyrosine kinase function and subsequent phosphorylation of intracellular target proteins, which results in proliferation of cells. 
It was also observed that the EGFR expression in the mucosa from HNSCC patients was less elevated when the epithelium was located more distant to the tumor. ,,
Elevated transforming growth factor-a mRNA
Besides the investigation of the EGFR also one of its ligands, transforming growth factor-a (TGF-a), was investigated. It was shown that the mRNA level of TGF-a was 5-fold increase in normal tumor-adjacent normal mucosa (TAM) compared with mRNA levels in control normal mucosa. 
One of the characteristics of the tumor is an increased proliferation. Shin et al.  showed a sequential increase in proliferating epithelial cells in normal tumor - associated mucosa in HNSCC patients using proliferating cell nuclear antigen and argyrophilic nucleolar organizer region.
This increase in proliferation was related rather to smoking than to the presence of an HNSCC as it was only detected in the TAM from smoking HNSCC patients. No increase was observed in TAM from nonsmoking HNSCC patients. This increase in proliferating cells was observed not only in TAM from smoking HNSCC patients but also in mucosa of the upper aerodigestive tract (UADT) from healthy smokers. 
Lack of Bcl-2 expression
Bcl-2, an apoptosis inhibitor, and its family members (among others, bax, an apoptosis inducer) play an important role in the regulation of the apoptotic pathway. 
According to Birchall et al.  there was the lack of Bcl-2 expression in HNSCC and in normal TAM compared with healthy control mucosa.
This lack is quite unexpected as one could anticipate an increase, but the authors suggest that the expression of Bcl-2 has to be interpreted in the context of levels of other Bcl-2 and Bax family members.
Increased glutathione S-transferase
The expression of gluthione S-transferase isoenzyme has been shown to be significantly higher in suprabasal and superficial layers of normal oral mucosa of HNSCC patients who subsequently developed SPTs as compared to its expression in normal mucosa from HNSCC patients who were free of disease after 7 years follow-up. The authors believe that this increase is intriguing as elevated levels of these detoxification enzymes actually protect against carcinogenic attacks, and probably, this might represent a futile effort for combating the carcinogenic metabolites in tobacco as all the patients studied had smoking habit. They believe that the reasons for high levels of this enzyme are not clear, but it seems to have a predictive value for the development of SPTs. 
Expression of the proto-oncogene product eIF4E
The protein has been found to be expressed at an elevated level in HNSCC. Furthermore, histologically normal margins of resected HNSCCs showed overexpression of eIF4E. 
Protein tyrosine kinase and protein tyrosine phosphatase activity
Normal TAM showed a 2.2-fold increase in protein tyrosine kinase activity compared to the control mucosa from healthy individuals. In addition, in the TAM, a 1.7-fold elevated ratio of protein tyrosine kinase activity to protein tyrosine phosphatise activity was observed. 
Nevertheless the promising marker for oral field cancerization is p53. Loss of function of the tumor suppressor p53 can result in uncontrolled cell division and progressive genomic instability. 
It has been found that the frequency of p53-positive cells gradually increases as oral epithelium progresses from normal to hyperplasia to dysplasia to carcinoma. ,
More than 90% of the HNSCCs contain mutated p53,  and in 50% of the tumors, loss of heterozygosity (LOH) of p53 has been show.  Abnormalities of the p53 tumor suppressor gene are among the most frequent molecular events in cancer. 
Focal p53 positivity was detected more often in normal TAM than in healthy control epithelium. 
Mutations in the p53 gene were identified in both normal TAM and tumor-distant mucosa from HNSCC patients, in contrast to healthy nonsmokers. These mutations were polyclonal and differed from those detected in the adjacent tumor. Focal overexpression of p53 might reflect an increased risk of SPTs in the patients. ,
If multiple tumors develop due to migration of malignant cells from a primary source, then the tumors and dysplasias from the same patient should show identical genetic alterations, whereas in case of independent origin, these alterations will be different. For these studies, various clonal markers have been used. 
To investigate the relationship between multiple primary tumors (MPTs), good clonal markers are needed. To qualify as a marker, such a genetic alteration should:
- Occur very early in the development of the primary lesion,
- Be maintained during progression of the lesion,
- Exhibit sufficient variability, and
- Be applicable in the majority of the lesions.
The clonal markers that fulfilled the above requirements are mainly x chromosome in activation, karyotypes of the tumor, LOH pattern and p53 mutation of these p 53 mutations are widely used clonal marker. p53 mutations are an early event in the development of HNSCC because they are already present in normal tissue distant from tumors, in normal tissue from healthy smokers, and in premalignant lesions. Thus, p53 mutations in HNSCC patients appear to be very useful as clonal marker, whereas the other markers are less suitable due to lack of variability and stability or due to technical requirements. 
Polyclonality of multiple primary tumors in the head and neck
Clonal markers are most commonly used to investigate the relationship between MPTs or to investigate dysplastic lesions occurring in the UADT and that were remote from each other showed polyclonality between these lesions. ,,,,
Waridel et al. observed All patients (16/16) presenting with multiple tumors had at least one positive biopsy, compared with only 53% (19/36) of patients presenting with single tumors (P < 0.001). This defines expansion of multiple clones of mutant p53-containing cells as an important biological mechanism of field cancerization, and provides a means to identify patients likely to benefit from intensive screening for the development of new head and neck tumours. 
Two patients with synchronous HNSCC tumors lying close to each other were investigated for clonality by van Oijen et al.  The first patient showed an identical p53 mutation and an identical LOH pattern in both tumors, whereas the other patient did not show identical aberrations. This strongly suggests that in the first patient, migration of malignant cells has occurred. Thus closer the lesion identical the genetic change.
Still polyclonolity or mono clonolity playing a role in causing these alterations are not clear cut, we have a clear evidence from so many studies conducted that shows there are fields in the oral mucosa that undergoes genetic alterations. Thus, it's not possible to remove all these areas surgically though we have protective measures which prevent causing DNA damage.
According to Papadimitrakopoulou et al.  Administration of 13-cis-retinoic acid for only 3 months yields a clinical response rate of 67% versus 10% for placebo. However, the toxicity is considerable, and there is a very high rate of relapse within 3 months of stopping treatment.
Several studies strongly suggest that fruits and vegetables have cancer-inhibitory properties for mouth and throat cancers. 
Several studies also reported cyclooxygenase-2 (COX-2) is overexpressed in head and neck squamous carcinoma, and COX-2 inhibitors prevent oral cancer. 
| Conclusion|| |
The role of field cancerization in causing malignant transformation has been well discussed in several studies. The presence of a field with genetically altered cells is a risk factor for cancer. A good research in this field has a strong potential to reveal new diagnostic markers for early detection, modalities to prevent progression, and lastly ways to combat development of SPTs (or second field tumors). To prevent field cancerization, habitual ingestion of carcinogens such as alcohol and cigarettes should be stopped, and longterm follow-up may be needed for patients treated with radiotherapy, chemotherapy, and teratogenic drugs such as retinoids.
| References|| |
Bremmer JF, Braakhuis BJ, Brink A, Broeckaert MA, Beliën JA, Meijer GA, et al.
Comparative evaluation of genetic assays to identify oral pre-cancerous fields. J Oral Pathol Med 2008;37:599-606.
Braakhuis BJ, Brakenhoff RH, Leemans CR. Second field tumors: A new opportunity for cancer prevention? Oncologist 2005;10:493-500.
Sugerman PB, Savage NW. Current concepts in oral cancer. Aust Dent J 1999;44:147-56.
Braakhuis BJ, Tabor MP, Leemans CR, van der Waal I, Snow GB, Brakenhoff RH. Second primary tumors and field cancerization in oral and oropharyngeal cancer: Molecular techniques provide new insights and definitions. Head Neck 2002;24:198-206.
Warren S, Gates O. Multiple primary malignant tumors. A survey of the literature and a statistical study. Am J Cancer 1932;16:1358-414.
Cunliffe WJ, Hasleton PS, Tweedle DE, Schofield PF. Incidence of synchronous and metachronous colorectal carcinoma. Br J Surg 1984;71:941-3.
Slaughter DP, Southwick HW, Smejkal W. Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer 1953;6:963-8.
Braakhuis BJ, Tabor MP, Kummer JA, Leemans CR, Brakenhoff RH. A genetic explanation of Slaughter′s concept of field cancerization: Evidence and clinical implications. Cancer Res 2003;63:1727-30.
Ha PK, Califano JA. The molecular biology of mucosal field cancerization of the head and neck. Crit Rev Oral Biol Med 2003;14:363-9.
Tabor MP, Braakhuis BJ, van der Wal JE, van Diest PJ, Leemans CR, Brakenhoff RH, et al.
Comparative molecular and histological grading of epithelial dysplasia of the oral cavity and the oropharynx. J Pathol 2003;199:354-60.
Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 1990;61:759-67.
van Oijen MG, Slootweg PJ. Oral field cancerization: Carcinogen-induced independent events or micrometastatic deposits? Cancer Epidemiol Biomarkers Prev 2000;9:249-56.
Nieburgs HE, Herman BE, Reisman H. Buccal cell changes in patients with malignant tumors. Lab Invest 1962;2:80-8.
Incze J, Vaughan CW Jr, Lui P, Strong MS, Kulapaditharom B. Premalignant changes in normal appearing epithelium in patients with squamous cell carcinoma of the upper aerodigestive tract. Am J Surg 1982;144:401-5.
Moll R, Franke WW, Schiller DL, Geiger B, Krepler R. The catalog of human cytokeratins: Patterns of expression in normal epithelia, tumors and cultured cells. Cell 1982;31:11-24.
van der Velden LA, Schaafsma HE, Manni JJ, Ramaekers FC, Kuijpers W. Cytokeratin expression in normal and (pre)malignant head and neck epithelia: An overview. Head Neck 1993;15:133-46.
Copper MP, Braakhuis BJ, de Vries N, van Dongen GA, Nauta JJ, Snow GB. A panel of biomarkers of carcinogenesis of the upper aerodigestive tract as potential intermediate endpoints in chemoprevention trials. Cancer 1993;71:825-30.
Ogden GR, Lane EB, Hopwood DV, Chisholm DM. Evidence of field change in oral cancer based on cytokeratin expression. Br J Oral Maxillofac Surg 1993;67:1324-30.
Bongers V, Snow GB, de Vries N, Braakhuis BJ. Potential early markers of carcinogenesis in the mucosa of the head and neck using exfoliative cytology. J Pathol 1996;178:284-9.
Bosch FX, Ouhayoun JP, Bader BL, Collin C, Grund C, Lee I, et al.
Extensive changes in cytokeratin expression patterns in pathologically affected human gingiva. Virchows Arch B Cell Pathol Incl Mol Pathol 1989;58:59-77.
Bloching MM, Soulsby H, Naumann A, Aust W, Merkel D, Braun T, et al.
Tumor risk assessment by means of immunocytochemical detection of early pre-malignant changes in buccal smears. Oncol Rep 2008;19:1373-9.
Izzo JG, Papadimitrakopoulou VA, Li XQ, Ibarguen H, Lee JS, Ro JY, et al.
Dysregulated cyclin D1 expression early in head and neck tumorigenesis: In vivo
evidence for an association with subsequent gene amplification. Oncogene 1998;17:2313-22.
Bartkova J, Lukas J, Müller H, Strauss M, Gusterson B, Bartek J. Abnormal patterns of D-type cyclin expression and G1 regulation in human head and neck cancer. Cancer Res 1995;55:949-56.
King LE Jr. What does epidermal growth factor do and how does it do it? J Invest Dermatol 1985;84:165-7.
Eisbruch A, Blick M, Lee JS, Sacks PG, Gutterman J. Analysis of the epidermal growth factor receptor gene in fresh human head and neck tumors. Cancer Res 1987;47:3603-5.
Grandis JR, Tweardy DJ. Elevated levels of transforming growth factor alpha and epidermal growth factor receptor messenger RNA are early markers of carcinogenesis in head and neck cancer. Cancer Res 1993;53:3579-84.
Christensen ME, Engbaek F, Therkildsen MH, Bretlau P, Nexø E. A sensitive enzyme-linked immunosorbent assay used for quantitation of epidermal growth factor receptor protein in head and neck carcinomas: Evaluation, interpretations and limitations. Br J Cancer 1995;72:1487-93.
Shin DM, Voravud N, Ro JY, Lee JS, Hong WK, Hittelman WN. Sequential increases in proliferating cell nuclear antigen expression in head and neck tumorigenesis: A potential biomarker. J Natl Cancer Inst 1993;85:971-8.
van Oijen MG, Gilsing MM, Rijksen G, Hordijk GJ, Slootweg PJ. Increased number of proliferating cells in oral epithelium from smokers and ex-smokers. Oral Oncol 1998;34:297-303.
Blandino G, Strano S. BCL-2: The pendulum of the cell fate. J Exp Clin Cancer Res 1997;16:3-10.
Birchall MA, Schock E, Harmon BV, Gobé G. Apoptosis, mitosis, PCNA and bcl-2 in normal, leukoplakic and malignant epithelia of the human oral cavity: Prospective, in vivo
study. Oral Oncol 1997;33:419-25.
Bongers V, Snow GB, de Vries N, Cattan AR, Hall AG, van der Waal I, et al.
Second primary head and neck squamous cell carcinoma predicted by the glutathione S-transferase expression in healthy tissue in the direct vicinity of the first tumor. Lab Invest 1995;73:503-10.
Franklin S, Pho T, Abreo FW, Nassar R, De Benedetti A, Stucker FJ, et al.
Detection of the proto-oncogene eIF4E in larynx and hypopharynx cancers. Arch Otolaryngol Head Neck Surg 1999;125:177-82.
Tonks NK, Charbonneau H. Protein tyrosine dephosphorylation and signal transduction. Trends Biochem Sci 1989;14:497-500.
Kirsch DG, Kastan MB. Tumor-suppressor p53: Implications for tumor development and prognosis. J Clin Oncol 1998;16: 3158-68.
el-Naggar AK, Lai S, Luna MA, Zhou XD, Weber RS, Goepfert H, et al.
Sequential p53 mutation analysis of pre-invasive and invasive head and neck squamous carcinoma. Int J Cancer 1995;64:196-201.
Shin DM, Kim J, Ro JY, Hittelman J, Roth JA, Hong WK, et al.
Activation of p53 gene expression in premalignant lesions during head and neck tumorigenesis. Cancer Res 1994;54:321-6.
Kropveld A, Rozemuller EH, Leppers FG, Scheidel KC, de Weger RA, Koole R, et al
. Sequencing analysis of RNA and DNA of exons 1 through 11 shows p53 gene alterations to be present in almost 100% of head and neck squamous cell cancers. Lab Invest 1999;79:347-53.
Erber R, Conradt C, Homann N, Enders C, Finckh M, Dietz A, et al.
TP53 DNA contact mutations are selectively associated with allelic loss and have a strong clinical impact in head and neck cancer. Oncogene 1998;16:1671-9.
Waridel F, Estreicher A, Bron L, Flaman JM, Fontolliet C, Monnier P, et al.
Field cancerisation and polyclonal p53 mutation in the upper aero-digestive tract. Oncogene 1997;14:163-9.
Colucci S, el-Gehani R, Flint S, Mothersill C. p53 mutations and protein expression in primary cultures of normal oral mucosa in smokers and non-smokers. Oral Oncol 1997;33:240-6.
Scholes AG, Woolgar JA, Boyle MA, Brown JS, Vaughan ED, Hart CA, et al.
Synchronous oral carcinomas: Independent or common clonal origin? Cancer Res 1998;58:2003-6.
Ribeiro U, Safatle-Ribeiro AV, Posner MC, Rosendale B, Bakker A, Swalsky PA, et al.
Comparative p53 mutational analysis of multiple primary cancers of the upper aerodigestive tract. Surgery 1996;120:45-53.
El-Naggar AK, Hurr K, Huff V, Clayman GL, Luna MA, Batsakis JG. Microsatellite instability in preinvasive and invasive head and neck squamous carcinoma. Am J Pathol 1996;148:2067-72.
Chung KY, Mukhopadhyay T, Kim J, Casson A, Ro JY, Goepfert H, et al.
Discordant p53 gene mutations in primary head and neck cancers and corresponding second primary cancers of the upper aerodigestive tract. Cancer Res 1993;53:1676-83.
van Oijen MG, Leppers Vd Straat FG, Tilanus MG, Slootweg PJ. The origins of multiple squamous cell carcinomas in the aerodigestive tract. Cancer 2000;88:884-93.
Papadimitrakopoulou VA, Hong WK, Lee JS, Martin JW, Lee JJ, Batsakis JG, et al.
Low-dose isotretinoin versus beta-carotene to prevent oral carcinogenesis: Long-term follow-up. J Natl Cancer Inst 1997;89:257-8.
Mayne ST. Beta-carotene, carotenoids, and disease prevention in humans. FASEB J 1996;10:690-701.
Tanaka T, Tanaka M, Tanaka T. Oral carcinogenesis and oral cancer chemoprevention: A review. Patholog Res Int 2011;2011:431246.