|Year : 2015 | Volume
| Issue : 3 | Page : 141-144
Oral field cancerization: An update of evidences
Balkuntla Krishnamurthy Ashwini, Prakash Sharada, Kyadala Nagaraja Hema, Srinivas Murthy Chitra
Department of Oral and Maxillofacial Pathology, AECS Maaruti College of Dental Sciences and Research Centre, Kammanahalli, Bengaluru, Karnataka, India
|Date of Web Publication||15-Sep-2015|
Balkuntla Krishnamurthy Ashwini
Department of Oral and Maxillofacial Pathology, AECS Maaruti College of Dental Sciences and Research Centre, #108, Hulimavu Tank Bund Road, B. T. M. 6th Stage, 1st Phase, Kammanahalli, Off. Bannerghatta Road, Bengaluru - 560 076, Karnataka
Source of Support: Nil., Conflict of Interest: None declared.
Patients with head and neck squamous cell carcinoma often develop multiple premalignant lesions; this led to the concept of field-effect in cancer which was originated by Slaughter et al. in the year 1953. Though this was based on histopathological observations, the development of modern molecular technologies has extended the field effect concept by exploring the molecular abnormalities in tissues that appear histologically normal. In this update, we discuss in detail about the origin, principle, various theories used to explain this effect, molecular findings and therapeutic implications related to oral field cancerization.
Keywords: Field cancerization, microsatellite markers, monoclonality, polyclonality
|How to cite this article:|
Ashwini BK, Sharada P, Hema KN, Chitra SM. Oral field cancerization: An update of evidences. J NTR Univ Health Sci 2015;4:141-4
| Introduction|| |
Head and neck squamous cell carcinoma (HNSCC) is one of the common malignancies in humans. The average 5-year survival rate is one of the lowest among aggressive cancers, and has not significantly improved during the last two decades. The term field cancerization was first put forward by Slaughter et al. in 1953. They examined 783 head and neck cancer patients to understand the epithelial changes beyond the boundaries of tumor, among which 11% of the patients demonstrated more than one independent area of malignancy. Slaughter et al. observed that cancer does not arise as an isolated cellular phenomenon, but rather as an anaplastic tendency involving many cells at once and develops at many foci as a result of repeated carcinogenic assault and progresses at various rates within the entire field. The concept now refers more broadly to a higher than expected prevalence of multiple local and distant primary tumors within the upper aero digestive tract, in addition to multiple oral premalignant lesions. Tobacco and alcohol use are independent risk factors, but when combined, they have a synergistic effect. Modern molecular techniques (karyotype analysis, microsatellite analysis, p53 mutation screening, and X chromosome inactivation studies) have refined the genetic basis of changes developed in mucosa exposed to the action of carcinogens, which prove to be more susceptible to the development of several foci of malignant transformation than in other mucous linings. In this article, we have tried to explain the theories of field cancerization and also discuss the molecular methods for detection of clonality and the therapeutic implications in relation to second primary tumors (SPTs).
| Oral Field Cancerization|| |
The principle behind this concept is that when the mucosa is exposed to carcinogens like tobacco and alcohol, an altered field results in which the epithelium has many independent foci of abnormal tissue that can give rise to potentially malignant and malignant lesions. There have been many proposed definitions and terminologies to this concept depending on its origin; it has been explained by many authors in terms of clonality.
The occurrence of multiple primary tumors (MPTs) could be attributed to independent molecular events affecting multiple cells in the entire field subsequent to exposure to carcinogens [Figure 1].
The molecular events occurring in a single progenitor with widespread expansion or lateral spread across the mucosa, two types of migration have been explained:
- Migration of tumor cells via saliva-micrometastasis [Figure 2]a.
- [Figure 2]b. Intra-epithelial migration of the progeny of the initially transformed cells [Figure 2]b.
Various studies have evaluated these two theories to understand which explains the concept of field cancerization the best.,
|Figure 2: Schematic representation of monoclonality theory (a) micrometastasis of tumor cells, (b) intra-epithelial migration of tumor cells|
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| Polyclonality|| |
Tumor-associated mucosa-margins associated with smoking harbor altered cells. Field changes like increase in the nuclear area, proliferation and p53 mutation, but these changes are seen in tumor free smokers. Epidemiologically, risk of developing SPTs is higher in smokers/drinkers compared with non-smokers/drinkers. The risk of development of SPT decreases when the patient quits smoking and alcohol.
| Monoclonality|| |
Common clonal origin in MPTs and is based on similarity of genetic changes. Three theories have tried to explain the same:
- Single cell/small clusters of cells migrate through submucosa.
- The cells are shed in the lumen of an organ at one place and regrow at another.
- Genetically altered field exists in the epithelium from which multiple clonally related neoplastic lesions develop which help in lateral clonal spread of cancer and subsequent occurrence of new primaries.
| Morphological Studies|| |
Slaughter et al. examined normal margins of excised specimens microscopically and found marked epithelial hyperplasia, hyperkeratinisation, atrophy, and fibrosis of submucosa. Dyskaryosis with marked atypia, in situ and carcinoma were also evident in areas adjacent to tumors that were studied. These findings evidences that they are multicentric in origin and represent lateral spread of oral squamous cell carcinoma. Further, a retrospective study conducted revealed the occurrence of MPTs in the mucosa of upper alimentary tract and respiratory tract. Therefore the authors suggested that oral squamous cell carcinoma originated by the concept of field cancerization where an area of epithelium shows irreversible changes in the cells which may have been exposed to an unknown carcinogen for a long duration. Incze et al. observed premalignant changes in normal epithelium of carcinoma patients at ultrastructural level, which were an increase in the nuclear area and altered nuclear cytoplasmic ratio. When Incze et al. observed smoker patient groups who developed synchronous and metachronous tumors and also those who had cancer at one site, they concluded that these changes were related to tobacco usage. Further when Kannan et al. studied mucosa adjacent to tumor in 15 cases, 67% demonstrated hyperplasia or mild dysplasia, whereas 33% showed moderate to severe dysplasia. At ultrastructural level, they also revealed sub cellular alterations similar to oral carcinomas. The most important observations were, bizarre nuclei of basal and lower spinal cells, enlarged and multiple nuclei, presence of interchromatin and perichromatin granules, loss of desmosomes with marked spongiosis, as well as disturbed cellular maturation evidenced by abnormal and irregular distribution of maturation markers like keratohyalin granules and tonofilaments.
| Clonality Studies|| |
Comparing the genetic alterations occurring in MPT's of the head and neck area will be helpful in assessing the strength of either the migration or the independency theory in explaining oral field cancerization. Various clonal markers have been used to identify if multiple tumors have developed due to migration of malignant cells from a primary source, the tumors then show identical genetic alterations, where as in case of independent origin, the alterations will be different. A good clonal marker is one which investigates the relation between MPT's and genetic alterations. To qualify as a marker, 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 determination of clonality initially was successful with karyotype analysis, detection of p53 and X chromosome inactivation. More recently, microsatellite alterations have been concluded as the most effective method to demonstrate clonality. They are the tandem repeat sequences found in noncoding region that are scattered randomly throughout the genome. p53 mutations help us to differentiate between recurrent/metastatic and SPT, p53 mutations occurs very early and a recurrent/metastatic tumor must retain the same mutation as the primary tumor, whereas independent tumors should display a different p53 gene status. This was again strengthened by studies conducted by Califano et al. and van Oijen et al., demonstrated the polyclonal nature of MPT in HNSCC using the loss of heterozygosity (LOH) patterns suggesting independent origin. Further, when studied using microsatellite assay with markers like 3p, 8p, 9p, 13q, identified the benign from the more troublesome true precursor lesions. Tabor et al. quantitatively measured LOH in HNSCC and described that at least 1/3 of patients have tumor-associated genetic alterations in biopsy taken from macroscopically normal mucosa adjacent to the tumor. Lee et al. also observed allelic loss of chromosome 13 in 10 samples out of 16. Hittelman et al. analyzed normal and malignant lesions adjacent to the head and neck tumors for chromosome instability using in situ hybridization and noted that molecular aberrations can be detected before histological evidence of morphological changes. Despite these molecular methods, specialized radiography like computed tomography, magnetic resonance imaging and positron emission tomography has been used extensively to detect SPT/secondary metastatic tumors.
| Clinical Relevance|| |
Second primary tumors/MPTs are cancers that are not connected by neoplastic epithelial changes from primary cancer; they can be synchronous, that is, tumors diagnosed simultaneously or within 6 months of the primary lesion or metachronous, that is, lesions that develop after 6 months of the original tumor. These lesions may alter the therapeutic approach to original tumors and can affect the prognosis of the same. The field change also creates a different view on tumor excision margins that contain molecularly altered cells. Even though tumor is removed completely, because it leaves remnants, recurrence may develop from the field of preconditioned epithelium. To combat field change effect, early detection of molecular changes before the development of clinical cancer becomes inevitable; the schematic diagram [Figure 3] enumerates the potential markers that can aid in detection of field changes.,
|Figure 3: Potential intermediate end point markers that aid in detection of field change|
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Taking all these into consideration, excising the established cancer is insufficient to prevent further disease but all the areas demonstrating molecular alterations cannot be removed. Thus, chemoprevention is an available alternative which could render the mucosa less sensitive to DNA alterations. Compounds like Cox-2 inhibitors and 13-cis-retinoic acid has been known to play a role in differentiation, development, and growth of epithelial cells. These compounds are under trial. However, cessation of smoking and alcohol should be advocated along with chemoprevention as it does have a role in the prevention of the malignancy.
| Conclusion|| |
Field cancerization poses a greater challenge, as it influences the morbidity and mortality of oral cancer patients. The presence of a field with genetically altered cells is a risk factor for cancer. The large number of preneoplastic cells in the proliferating fields is likely to increase cancer risk dramatically. The probability of developing a second primary tumor in a patient who once had head and neck squamous cell cancer is around 20%. Further 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 second primary tumor. Early identification and management of field change is a vital determinant for prevention of cancer mortality and morbidity.
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[Figure 1], [Figure 2], [Figure 3]