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 Table of Contents  
REVIEW ARTICLE
Year : 2015  |  Volume : 6  |  Issue : 1  |  Page : 35-40

Field effect in oral cancer: An update


Department of Oral Pathology, SRM Dental College, Ramapur am, Chennai, Tamil Nadu, India

Date of Web Publication19-Jan-2015

Correspondence Address:
Ramya Malini
Department of Oral Pathology, SRM Dental College, Ramapuram, Chennai - 600 089, Tamil Nadu
India
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DOI: 10.4103/0976-433X.149589

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  Abstract 

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 Top


Oral cancer is a significant public health threat accounting for 270,000 new cases annually worldwide. [1] 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. [2]

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. [3]


  Clinical definition of locally recurrent cancer Top


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. [4]


  Clinical definition of second primary tumors Top


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. [5]


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. [4]

According to Cunliffe et al. [6] 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.

Field cancerization

In their classical paper of 1953, Slaughter et al., [7] 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. [8]

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. [9]

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." [10]

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. [11]

Three theories have been proposed to explain the occurrence of the multiple tumors:

  1. Monoclonal theory where multiple genetically related tumors arise from a single cell through mucosal spread.
  2. Polyclonal theory in which multiple transforming events give rise to genetically unrelated multiple tumors.
  3. 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. [8],[12]



  Oral field changes and their relationship with risk factors Top


Morphological changes

In 1962, Nieburgs et al. [13] 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. [14] 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. [15],[16]

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. [17],[18],[19],[20]

Changes in blood group antigens of the ABH system

In a study by Bongers et al., [19] 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. [21]

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. [22]

Bartkova et al. [23] 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. [24]

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. [25],[26],[27]

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. [26]

Increased proliferation

One of the characteristics of the tumor is an increased proliferation. Shin et al. [28] 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. [29]

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. [30]

According to Birchall et al. [31] 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. [32]

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. [33]

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. [34]

p53 overexpression

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. [35]

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. [36],[37]

More than 90% of the HNSCCs contain mutated p53, [38] and in 50% of the tumors, loss of heterozygosity (LOH) of p53 has been show. [39] Abnormalities of the p53 tumor suppressor gene are among the most frequent molecular events in cancer. [12]

Focal p53 positivity was detected more often in normal TAM than in healthy control epithelium. [12]

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. [40],[41]

Clonality studies

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. [12]

Clonal markers

To investigate the relationship between multiple primary tumors (MPTs), good clonal markers are needed. To qualify as a marker, such a genetic alteration should:

  1. Occur very early in the development of the primary lesion,
  2. Be maintained during progression of the lesion,
  3. Exhibit sufficient variability, and
  4. 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. [12]

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. [29],[42],[43],[44],[45]

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. [41]

Two patients with synchronous HNSCC tumors lying close to each other were investigated for clonality by van Oijen et al. [46] 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.

Chemoprevention

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. [47] 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. [48]

Several studies also reported cyclooxygenase-2 (COX-2) is overexpressed in head and neck squamous carcinoma, and COX-2 inhibitors prevent oral cancer. [49]


  Conclusion Top


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.

 
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