Oral Field Cancerization and Its Clinical Implications in the Management in Potentially Malignant Disorders.

Oral cancer is one of the common malignancies reported in India. Most of these cancers are preceded by potentially malignant disorders. Despite improvements in the management strategies of these cancers the posttreatment prognosis has remained poor. The 5-year survival rates of oral cancers in most countries are still below 50%. The poor outcomes in oral cancer prevention and treatment can be due to nature of the spread of genetically altered cells as fields within the epithelial compartment. The conventional management protocols need to be modified taking into consideration the field spread of genetically altered cells.

INTRODUCTION

Oral cancer is estimated to be the third most common malignancy in India. It ranks as the second most common malignancy among males and fourth most common malignancy among females.[1] More than 90% of oral cancers among men can be attributed to tobacco use.[2] The survival rates of treated oral cancer cases have not improved much even after decades of research and development in the management of these disorders. The 5-year survival rates of oral cancers in most countries are still below 50%. This high failure in the treatment of oral cancers is due to delay in the diagnosis and emergence of the second primary tumors (SPTs).[3] Recent studies have shown that 20 years within the diagnosis of primary oral cancer 30% of male patients, and 20% of female patients developed the second primary tumor.[4] It is estimated that 50% of oral cancers develop from precursor lesions. Early diagnosis and effective management of potentially malignant disorders are important in preventing cancer. However, when the long-term outcomes of surgically treated precancer lesions were evaluated, it was found that despite treatment there is no reduction in the rate of malignant transformation. The reason for the poor prognosis and treatment outcomes of oral precancers and cancers can be explained in part by the concept of field cancerization popularized by Slaughter et al.[56]

This article aims in reviewing the concepts of field cancerization, its role in the prognosis of oral cancers and precancers and its implication in the patient management.

WHAT IS FIELD CANCERIZATION?

The concept of field cancerization was introduced by Slaughter et al. He found histologically altered tissue surrounding squamous cell carcinoma. This concept was used to explain the development of multiple primary tumors and recurrent local tumors.[6] The recent developments in molecular biology have made us to understand the genetic basis of the multistep carcinogenesis. It has been estimated that around five genetic mutations are needed to transform a normal epithelial cell to a malignant one. Loss of chromosomal material in 3p, 9q, and 17p was seen more frequently in dysplastic lesions and are considered as early markers of carcinogenesis. The loss of 13q and 8p was frequently seen with carcinomas and are considered as late changes.[78]

In view of these genetic alterations in multistage carcinogenesis, Boudewin et al. proposed an updated model of field cancerization. The stem cells in the proliferative basal layer, its daughter cells which form the transiently amplifying cells and terminally differentiated cells altogether form the clonal unit. They are a cluster of <200 cells with 2 mm in diameter. The p53 gene mutations were found to be an early event in the oral carcinogenesis. Van Houton found clones of cells bearing p53 gene mutations. These clonal units of mutated cells are called patches. As these altered cells acquire more mutations, they acquire growth advantage over their normal counterparts. The patches of altered cells start to spread laterally, replacing the normal epithelial cells within the epithelial compartment. These genetically altered epithelial cells are called as fields. The size of these fields can range from 4 mm to 7 cm. The fields never show invasive growth. Subsequent accumulation of mutations within the fields can lead to the formation of subclones which are genetically altered enough to become invasive carcinoma with metastatic potential.[910]

WHAT ARE SECOND PRIMARY TUMORS AND FIELD TUMORS?

The poor treatment outcomes of oral squamous cell carcinomas are attributed mainly to the development of SPTs. The criteria proposed by Warren and Gates are used to define SPTs. They are (1) each of the tumor should present a definite picture of the malignancy, (2) each must be distinct, and (3) the probability of one being the metastasis of the other should be excluded.[11] Based on these criteria, when a tumor is developed 2 cm away from the index tumor or if the time taken for the second carcinoma to occur is more than 3 years, it is considered to be an SPT. When the second tumor is formed from the same field of the primary tumor, it is referred as a second field tumor (SFT).[9]

Based on the insights into the genetic aspects of field cancerization, Bodjwin proposed a molecular classification of SPT. If the second tumor is formed in the same anatomic site of the primary tumors, it will be considered as follows: (a) recurrent tumor – if all the molecular aberrations are similar. (b) SFT – some genetic markers are similar, but later there is a divergence; and hence, other markers are different. (c) SPT – all the genetic markers are different.

If the second tumors are formed in the different anatomic site, it is considered as follows: (a) metastasis – if all the molecular aberrations are similar. (b) SFT – some genetic markers are similar, but later there is a divergence; and hence, other markers are different. (c) SPT – all the genetic markers are different.[11]

FIELD CANCERIZATION IN POTENTIALLY MALIGNANT DISORDERS

The genetic model of multistage carcinogenesis has shown that premalignant lesions and conditions are an intermediate stage in cancer development. The lesional cells in this stage harbors genetic aberrations of early carcinogenesis.[9] Lydiatt et al., on studying the fields surrounding oral lesions found that even clinically normal appearing mucosa harbors early precancerous genetic aberrations.[12]

The conventional terminology considered precancerous lesions as morphologically altered areas from where cancers will arise. Precancerous conditions were defined diseases where oral cancer can arise from any part of the oral cavity.[13] Considering the new evidences, the international working group in oral cancer and precancer proposed change in terminology. Since clinically normal appearing mucosa can harbor genetic mutations forming a field near the precancerous lesion, oral cancer can occur even from an adjacent clinically normal appearing mucosa. They recognized that there is no advantage in subdividing precancer to lesions and conditions. They proposed that all the clinical conditions that carry the risk of oral cancer development can be termed as potentially malignant disorders.[14]

FIELD CANCERIZATION AND ITS CLINICAL IMPLICATIONS IN THE MANAGEMENT OF POTENTIALLY MALIGNANT DISORDERS

The current treatment protocols for potentially malignant disorders such as leukoplakia are centered on the removal of the morphologically altered area. This management strategy is based on the belief that oral cancers will occur on the morphologically altered area.[13] However, the current evidence shows that the adjacent clinically normal appearing mucosa also harbors genetic aberrations of early malignant transformation.[12] These fields of cancerization can extend from 4 mm to 7 cm.[9]

Based on these newer insights, we would like to reinforce the following management strategies along with the conventional surgical removal of morphologically altered lesion.

Counseling and reinforcement during follow-up visits regarding habit cessation. The continued exposure to tobacco carcinogens will induce more genetic mutations to the already existing precancer fields[2]

Emphasis should be placed on long-term follow-up and monitoring of the patients. It is estimated that it takes 67–96 months to transform into an invasive carcinoma[10]

Importance should be given in the examination of the whole oral cavity not only the lesional area.

CONCLUSION

The current developments in the genetic aspects of multistage carcinogenesis and field cancerization have made a rethink in the nomenclature and behavior of these diseases. Understanding these developments in the field of oral cancer and precancers will improve the clinician's management strategies. A reemphasis on the importance of habit cessation, long-term follow-up and the examination of clinically normal appearing mucosa during follow-ups can help in the early detection of malignant changes. These steps should help in improving the prognosis of the patients with potentially malignant disorders. The future development should be aimed at incorporation of relevant molecular markers in the assessment of potentially malignant disorders and the use of minimally invasive brush biopsy techniques to identify field lesions.

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Nil.

Conflicts of interest

There are no conflicts of interest.