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 Table of Contents  
REVIEW ARTICLE
Year : 2016  |  Volume : 3  |  Issue : 4  |  Page : 247-251

Field cancerization in stomatognathic system


1 Department of Oral Pathology and Microbiology, School of Dental Sciences, Krishna Institute of Medical Sciences University, Karad, Satara, Maharashtra, India
2 Department of Public Health Dentistry, School of Dental Sciences, Krishna Institute of Medical Sciences Deemed University, Karad, Satara, Maharashtra, India

Date of Web Publication14-Sep-2016

Correspondence Address:
Dr. Vidya Kadashetti
Department of Oral Pathology and Microbiology, School of Dental Sciences, Krishna Institute of Medical Sciences University, Malkapur, Karad, Satara - 415 110, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2348-3334.190580

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  Abstract 

Worldwide, head and neck squamous cell carcinoma is the sixth most common malignancy in men. The parts of Southeast Asia, head and neck squamous cell carcinoma is the most common malignancy, accounting for up to 50% of malignant tumors. Oral squamous cell carcinoma is believed to arise from a series of genetic changes induced by carcinogens, ultimately leading to clinical and microscopic changes summating to form an invasive neoplasm. The principal etiological factors such as tobacco and alcohol are responsible for DNA mutation activating oncogenes interfering with tumor suppressor genes and interacting with various epithelial growth factors. Slaughter in 1953 proposed the concept of field cancerization. He hypothesized that an area of epithelium is preconditioned by a carcinogenic agent. Such a carcinogenic influence if operative long enough in time and intense enough in exposure produce an irreversible change in cells and cell groups in a given area and so that the process toward cancer becomes inevitable. Thus, oral squamous cell carcinoma is multicentric in origin, through a process of field cancerization would seem to be an important factor in the persistence or recurrence of oral squamous cell carcinoma. As local and systemic therapies for primary tumor do not appear to prevent multifocally, the prognostic implications of field cancerization change may be substantial. The occurrence of second primary tumors may not be the major cause of mortality in the head and neck cancer patients but has a high impact on mortality and the treatment program of these patients. Careful screening procedures, carried out to detect multifocal tumors at an early stage, should improve survival in these patients.

Keywords: Carcinoma, field cancerization, head and neck squamous cell carcinoma


How to cite this article:
Kadashetti V, Shivakumar K M, Baad R, Vibhute N, Belgaumi U, Sushma G, Patil S. Field cancerization in stomatognathic system. CHRISMED J Health Res 2016;3:247-51

How to cite this URL:
Kadashetti V, Shivakumar K M, Baad R, Vibhute N, Belgaumi U, Sushma G, Patil S. Field cancerization in stomatognathic system. CHRISMED J Health Res [serial online] 2016 [cited 2019 May 19];3:247-51. Available from: http://www.cjhr.org/text.asp?2016/3/4/247/190580


  Introduction Top


Worldwide, head and neck squamous cell carcinoma is the sixth most common malignancy in men and accounts for approximately 5% of malignant tumors in the population of developed countries.[1] However, in parts of Southeast Asia, head and neck cancer is the most common malignancy, accounting for up to 50% of malignant tumors. These percentages reflect the prevalence of the specific risk factors in these geographic regions: Tobacco and alcohol in the developed countries and chewing of betel-quid in Southeast Asia. Studies of the epidemiology of the head and neck squamous cell carcinoma have identified tobacco and alcohol use as independent risk factors, but when both factors are combined, there is a synergistic effect. The oral cavity is one of the prevalent sites for the development of potentially malignant disorders. It is well known that these premalignant pathologies may progress to invasive carcinomas. Field cancerization is a well-known and well-documented process of malignant transformation.[2],[3],[4],[5],[6]

The term “field cancerization” was proposed by Slaughter et al. in 1953; Slaughter et al. originally elucidated the concept of field cancerization to account for their observations of multifocal squamous cell carcinoma in the oral cavity. They proposed that oral squamous cell carcinoma developed in a multifocal fashion within a field cancerization of tissue bathed by carcinogens. Based on his findings of abnormal and hyperplastic, often atypical, epithelium surrounding oral squamous cell carcinoma for varying distances and finding of multiple independent tumors in oral squamous cell carcinoma patients. He hypothesized that an area of epithelium is preconditioned by a carcinogenic agent. Such a carcinogenic influence if operative long enough in time and intense enough in exposure produce an irreversible change in cells and cell groups in a given area and so that the process toward cancer becomes inevitable.[7] This concept (also called field cancerization carcinogenesis or condemned-mucosa syndrome) may explain the clinical occurrence of multiple primary and second primary tumors in the head and neck squamous cell carcinoma. Data indicate that second primaries, whether synchronous or metachronous, generally are of squamous histology, develop at a constant rate (4–7% of treated patients per year), are not treatment related, and occur in the aerodigestive field cancerization at risk, that is, the head and neck, the upper two-thirds of the esophagus, and the lung. These characteristics of second primaries support the field cancerization hypothesis.[8],[9],[10],[11]

Recent data on p53 mutations provide strong molecular support for the field cancerization carcinogenesis concept. Despite epidemiologic studies having long associated tobacco and alcohol use with the development of head and neck squamous cell carcinoma, the molecular targets of these agents remain to be identified.[11],[12] In recent investigations by Brennan et al., significant tobacco and alcohol use was associated with a high frequency of p53 mutations. Their preliminary results suggest these p53 mutations occur at nonendogenous mutation sites.[13],[14],[15] These findings suggest a role for tobacco in the molecular progression and field cancerization carcinogenesis process in head and neck cancer. Some studies have established an association among genetic alterations as the loss of heterozygosity (LOH), microsatellite and chromosomal instability and p53 gene mutations in macroscopically normal tumor-adjacent areas. The presence of a field cancerization containing genetically altered cells represents a continuous risk factor to the growth of secondary cancers.[1],[10],[16],[17] The purpose of this review is to present a field cancerization occurring independently anywhere in oral mucosa or aerodigestive tract.


  Oral Field Cancerization Theories Top


Slaughter et al. hypothesized that the entire epithelial surface of the upper aerodigestive tract (UADT) has an increased risk for the development of premalignant lesions because of multiple genetic abnormalities in the whole tissue region due to be the result of exposure to carcinogens that caused multiple genetic abnormalities in the whole tissue region.[7] The multiple squamous cell lesions described in the oral field cancerization process were thought to have developed independently of each other. The occurrence of multiple premalignant lesions has been proposed in the last decade and is based on the premise that any transforming event is rare and that the multiple lesions arise due to the widespread migration of transformed cells through the whole aerodigestive tract.[10],[16],[17] Two types of migration might be involved in this concept: (a) Migration of tumor cells by, for example, saliva (micrometastases); or (b) intraepithelial migration of the progeny of the initially transformed cells. The “field cancerization” theory tries to explain the risk of local recurrences and development of second primary tumors in oral squamous cell carcinoma patients. According to this theory, it is assumed that clinically normal mucosa adjacent to oral cancer has already developed certain premalignant histopathological changes. Some studies suggest that precursor lesions may appear at any part of the oral mucosa exposed to carcinogens.[18],[19] The field of genetically altered cells in patients with squamous cell carcinoma called “field cancerization,” has been documented with numerous clinical, histopathological and molecular studies.[1],[18] Therefore, the patients with head and neck squamous cell carcinoma are subject to the risk of developing local recurrences or second primary tumors as a consequence of the field cancerization, which is considered to be a bad prognostic sign. Therefore, according to the concept of the field cancerization, it is assumed that clinically normal mucosa adjacent to oral cancer has suffered certain histopathological changes, as well as molecular, which can be the cause for the development of multiple premalignant lesions.[20] If metastatic cells from a Head and Neck Squamous cell carcinoma migrate through the blood or lymphatic system, they usually settle in the lung or in the first lymph node encountered. Therefore, this route would not lead to tumor deposits in the mucosal surface that lines the UADT.[7],[21],[22]


  Molecular Support for Field Cancerization Top


Changes in blood group antigens of the ABH system

Type 2 chain histo-blood group (ABH) carbohydrate structures are distributed broadly in epithelial and endothelial cells, independent of the patient's ABO blood group. In normal oral and laryngeal epithelium, type 2 chain ABH-antigens are expressed on parabasal cells. 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 the head and neck squamous cell carcinoma, compared with healthy individuals. Because the ABH type 2 chain expression was always lower in the mucosa from the patients than in the mucosa from healthy controls, this antigen may be promising as a negative marker for field change and risk indication.[23],[24],[25]

Foci of cyclin D1 expression

Cyclins are cell cycle regulators that are functional only when associated with CDKs. Cyclin D1 regulates the G1-S transition in the cell cycle and is functional when it is associated with either CDK4 or CDK6. Cyclin D1 amplification has been shown in premalignant lesions, and the amplification frequency progresses from premalignant lesions to invasive carcinoma. Braakhuis et al. observed clearly defined foci of cyclin D1 expression in sections of normal mucosa adjacent to head and neck squamous cell carcinoma that were not seen in sections of normal mucosa from healthy individuals this will be the positive marker for field cancerization change and risk indication.[4],[26],[27]

p53 overexpression

Loss of function of the tumor suppressor p53 can result in uncontrolled cell division and progressive genomic instability. Prognostic value of Ki67 has been shown in several kinds of cancer. However, some studies showed the lack of association between the immune expression of p53 and Ki67 in mucosa and invasive front, which possibly indicates independent roles of both proteins. So not only changes in p53 protein promote altered cell proliferation, but also other disturbances in cellular metabolic pathways should also happen to trigger the disordered mitotic activity Abnormalities of the p53 tumor suppressor gene are among the most frequent molecular events in cancer. More than 90% of the head and neck squamous cell carcinoma cells contain mutated p53, and in 50% of the tumors, LOH of p53 has been shown. The frequency of p53 positive cells gradually increases as oral epithelium progresses from normal to hyperplasia to dysplasia to carcinoma. Focal p53 positivity was detected more often in the adjacent surface of carcinoma patients than in healthy control epithelium. These mutations were polyclonal and differed from those detected in the adjacent tumor.[10],[28],[29],[30] Focal overexpression of p53 might reflect an increased risk of second primary tumors in these patients. Furthermore, p53 expression above the basal cell layers in oral mucosa has been found to be an early event of malignant transformation and has predictive value for the development of head and neck squamous cell carcinoma. Elevated transforming growth factor alpha (TGF-α) mRNA was investigated in normal mucosa and tumour associated mucosa. It was shown that the mRNA level of TGF-α mRNA was 5-fold increased in tumour associated mucosa compared with mRNA levels in control normal mucosa, but whether this relates to smoking or tobacco users is unknown.[17],[31],[32],[33],[34],[35],[36]

Finally, p53 mutations have been used as a clonal marker p53 mutations are an early event in the development of head and neck squamous cell carcinoma because they are already present in normal tissue distant from tumors, in normal tissue from healthy smokers, and in premalignant lesions. These mutations are diverse enough and stable during metastasizing. Thus, p53 mutations in head and neck squamous cell carcinoma patients appear to be very useful as clonal marker, whereas the other markers are less suitable due to the lack of variability and stability or due to technical requirements.[2],[7],[17],[37],[38]


  Discussion Top


In field cancerization, an area of epithelium has been preconditioned by long-term exposure to carcinogens. In this preconditioned epithelium, multifocal carcinomas can develop as a result of independent mutations and this would not be genetically related. Thus, the carcinoma occurs from multifocal areas of precancerous change and not from one cell that suddenly becomes malignant. It is well accepted that the progression from normal to cancer cell is a multistep process in carcinogenesis.[7],[12]

Field cancerization was traditionally defined as “increased risk of cancer development in the entire UADT due to multiple genetic abnormalities in the whole region after prolonged exposure to carcinogen.”[7] More recently, Braakhuis et al.[4] have proposed a definition based on molecular findings. Field lesion means the presence of one or more areas consisting of epithelial cells that have genetic alterations.[7],[39] The concept of field cancerization can be interpreted as follows: In the “classical view,” large areas of the aerodigestive tissue are affected by long-term exposure to carcinogens. In this preconditioned epithelium, multifocal carcinomas can develop as a result of independent mutations, and thus would not be genetically related.[40],[41],[42],[43],[44] An “alternative” view, also known as “clonal theory” tells a single cell is transformed and gives rise to one large, extended, premalignant field by clonal expansion, and gradual replacement of normal mucosa.[34] The second theory was further elaborated by Monique granular convoluted tubule van Oijen and Slootweg in 2000,[1] which were explained on the basis of two types of migration of already genetically transformed cells: Migration of tumor cells by, for example, saliva (micrometastasis), intraepithelial migration of the progeny of the initially transformed cells.


  Clinical Implications Top


The presence of a field cancerization with genetically altered cells is a risk factor for cancer. The large number of preneoplastic cells in the proliferating field cancerization is likely to increase cancer risk dramatically.[20] The probability of developing a second primary tumor in a patient who once had head and neck squamous cell cancer is around 20%. Cancer begins with multiple cumulative epigenetic and genetic alterations, leading to sequential cellular transformations. The early genetic events might lead to a clonal expansion of premalignant daughter cells in a particular tumor field cancerization. Subsequent genomic changes in some of these cells drive them toward the malignant phenotype. Histologically, these transformed cells are diagnosed as cancer owing to alterations in their morphology.[45],[46],[47],[48] Thus, a population of daughter cells with early genetic changes (without histological changes) remains in the organ, demonstrating the concept of Field cancerization. For early detection of cancer, one can rely on tumor markers. However what is important, in the context of Field cancerization, is the identification of molecular signatures in the genetically transformed but histologically normal cells (peri-tumoral cancer Field cancerization). Hence, identification of such tumor-specific biomarkers will have excellent utility in monitoring the tumor progression and if possible, in preventing transformation of premalignant lesions into invasive cancer.[7],[15],[49],[50]


  Conclusion Top


The presence of a field cancerization with genetically altered cells is a risk factor for cancer. Conditions like oral submucous fibrosis that involves considerably larger mucosal areas predispose to development of field cancerization or multiple primaries. The theory of field cancerization suggests that there is an increased likelihood of concurrent or future disease in patients with head and neck lesions. Therefore, it is incumbent on the care providers to be more diligent about screening and directed biopsies in these patients. It should be taken into account in treatment planning of a patient with cancer so that all treatment options, including the use of radiation therapy, kept open as long as possible in the event that the patient may develop multiple primary tumors. A good research in this field cancerization has a strong potential to reveal new diagnostic markers for early detection, modalities to prevent progression, and finally ways to combat the development of second primary tumor (or second field cancerization tumors). Finally, not only early detection and management of oral cancer are important but equally important are early identification and management of a field cancerization, so as to have profound implications on cancer prevention and outcome of the treatment.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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