Archives of Medicine and Health Sciences

REVIEW ARTICLE
Year
: 2013  |  Volume : 1  |  Issue : 2  |  Page : 136--139

Field cancerization: A review


M Aparna, Prashanth Shenai, Laxmikanth Chatra, KM Veena, Prasanna Kumar Rao, Rachana V Prabhu, KA Shahin 
 Department of Oral Medicine and Radiology, Yenepoya Dental College, Yenepoya University, Deralakatte, Mangalore, Karnataka, India

Correspondence Address:
Laxmikanth Chatra
Department of Oral Medicine and Radiology, Yenepoya Dental College, Yenepoya University, Deralakatte, Mangalore - 575 018, Karnataka
India

Abstract

Concept of field cancerization was first introduced over six decades ago in the setting of oral cancer. Later, field cancerization involving histologic and molecular changes of neoplasms and adjacent tissue was explained. Field cancerization involves the lateral spread of pre-malignant or malignant disease and contributes to the recurrence of head and neck tumors. The overall hypothesis underlying this work is that endothelial cells actively participate in tumor cell invasion by secreting chemokines and creating a chemotactic gradient for tumor cells. The article tries to explain the conflicting aspects of field cancerization in the setting of oral cancer.



How to cite this article:
Aparna M, Shenai P, Chatra L, Veena K M, Rao PK, Prabhu RV, Shahin K A. Field cancerization: A review.Arch Med Health Sci 2013;1:136-139


How to cite this URL:
Aparna M, Shenai P, Chatra L, Veena K M, Rao PK, Prabhu RV, Shahin K A. Field cancerization: A review. Arch Med Health Sci [serial online] 2013 [cited 2020 Mar 28 ];1:136-139
Available from: http://www.amhsjournal.org/text.asp?2013/1/2/136/123026


Full Text

 Introduction



The term "field cancerization" was introduced in 1953 to describe histologically abnormal tissues surrounding oral squamous cell carcinoma, particularly in the upper aerodigestive tract, likely related to exposure to carcinogens. [1] The term "lateral cancerization" was subsequently used to indicate that the lateral spread of tumors was due to progressive transformation of cells adjacent to a tumor, rather than the spread and destruction of the adjacent epithelium by pre-existing cancer cells. [2] Development of multiple cancer is commonly associated with the concept of field cancerization, in which several tumors develop at different distant sites due to gene aberration induced by carcinogens such as alcohol and cigarettes, but not by metastasis of tumor cells. [3] Identification of distinct biological markers that can help to predict field change is now considered a prime requisite. [4] Chemoprevention is the use of natural or synthetic substances to halt, delay, or reverse malignant progression in tissues at risk to develop invasive cancer. [5],[6],[7] Understanding the concept of field cancerization, its risk factors, biologic markers, and chemoprevention methods in oral cavity will help to reduce devastating effects of oral malignancy.

 Oral Field Cancerization



The term field cancerization has been utilized to explain the followings: (a) Oral cancer developing in multifocal areas of a pre-cancerous change; (b) abnormal tissues surrounding the tumor; (c) oral cancer often consisting of multiple independent lesions that may coalesce; (d) the persistence of abnormal tissue even after surgery may explain secondary primary tumor and recurrences. [8] The criteria used to diagnose multiple primary carcinomas, as originally described by Warren and Gates and modified by Hong et al., were as follows: (a) Each neoplasm must be anatomically separate and distinct (if the intervening mucosa demonstrates dysplasia, it is considered a multicentric primary neoplasm); (b) the possibility that the second primary carcinoma represents a metastasis or a local relapse must be excluded. It has to be separated from the first by at least 2 cm of normal epithelium or has to occur at least 3 years after the first diagnosis. [9],[10] The concept of field cancerization can be interpreted in different ways to explain phenomenon of secondary primary tumors: (a) In classic view, large areas of aerodigestive tissue are affected by long-term exposure to carcinogens. In this pre-conditioned epithelium, multifocal carcinomas can develop as a result of independent mutations; (b) in terms of clonal theory, a single cell is transformed and gives rise to one large, extended, pre-malignant field by clonal expansion and gradual replacement of normal mucosa. This theory was elaborated by Monique GCT van Oijen et al. in 2000, which was explained on the basis of two types of migration of already genetically transformed cells: (a) Migration of tumor cells; (b) intraepithelial migration of the initially transformed cells. [11]

 Distant Lesions



High incidence of recurrence observed in patients with this disease is due to the distinctive ability of head and neck cancer cells to migrate and persist outside the field of treatment. The phenomenon of field cancerization observed in head and neck tumors can be caused either by molecular events affecting several cells from different locations at the same time or by molecular events in a single clonal progenitor that is capable of widespread clonal expansion or lateral spread. [12],[13] The process of local tumor spread has been associated with epithelial-mesenchymal transition, a conserved morphogenic process that involves loss of E-cadherin function that contributes to the migration of individual tumor cells. [13],[14],[15] Kristy A Warner et al. in their study demonstrated that CXC chemokines secreted by tumor-associated endothelial cells induce tumor cell invasion through CXCR2. Bcl-2 upregulation correlates with increased expression of CXCL1 and CXCL8 in endothelial cells. The results in the study position the neovascular endothelial cells as the source of a chemotactic gradient that will induce tumor cell movement away from its original niche. [16]

 Risk Factors



In chronic inflammatory diseases like oral lichen planus (OLP), there is chronic inflammation and immune activation. Activated inflammatory cells and cytokine network promote squamous tumerogenesis, influence clonal spreading, and thus support process of field cancerization. [17] Tobacco can cause morphological changes in cells of normal buccal mucosa in patients with malignant disease. The changes include increase in nuclear size, discontinuous nuclear membrane, numerous Feulgen-negative areas, increase in associated chromatin surrounding clear areas, absence of a single large nucleolus and altered nuclear-cytoplasmic ratio. [18] Abnormalities of the p53 tumor suppressor gene are among the most frequent molecular events in cancer. Focal over expression of p53 occurred more frequently in normal epithelium from smoking head and neck squamous cell carcinoma (HNSCC) patients than from non-smoking HNSCC patients and from healthy control individuals. [19] 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 HNSCC, 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. [18],[20],[21]

Early detection and prevention

For early detection of a cancer, one can rely on tumor markers. But what is important, in the context of field cancerization, is identification of molecular signatures in the genetically transformed but histologically normal cells (peri-tumoral cancer field). Identification of such tumor-specific biomarkers will have excellent utility in monitoring the tumor progression and, if possible, in preventing transformation of pre-malignant lesions into invasive cancer [Table 1].{Table 1}

Investigations

Field cancerization can be demonstrated by supravital staining by toluidine blue or by electron microscopic study of random biopsies taken from apparently normal mucosa. [23]

Chemoprevention

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. Subsequent studies with retinoids in patients with oral pre-malignant lesions have confirmed clinical and pathologic response rates, though toxicities remain a concern. [24] Observational studies strongly suggest that fruits and vegetables have cancer-inhibitory properties for mouth and throat cancers. Human intervention trials using beta-carotene in the prevention and/or reversal of oral micronuclei and oral leukoplakia (precancerous changes) lend further credence to the hypothesis that beta-carotene is at least one of the agents responsible for protective effects of fruits and vegetables. [25] [Figure 1] EGFR is a receptor tyrosine kinase that is overexpressed in oral dysplasia and invasive cancer and associated with poor prognosis in patients with head and neck squamous carcinoma. EGFR inhibitors, alone or in combination with chemotherapy and radiotherapy, show activity against head and neck squamous carcinoma. Several studies reported COX-2 is overexpressed in head and neck squamous carcinoma, and COX-2 inhibitors prevent oral cancer. [22] Reversal of epigenetic events with agents such as hydralazine, 5-Aza-2'-deoxycytidine, zebularine, and magnesium valporate is possible. Knowledge of methylation patterns and their role in malignant transformation will enable controlled use of mehtylation reversal agents in primary chemoprevention[26].{Figure 1}

 Conclusion



The process of formation of oral cancer results from multiple sites of pre-malignant change in the oral cavity (field cancerization). 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 second primary tumor (or second field tumors). To prevent field cancerization, habitual ingestion of carcinogens such as alcohol and cigarettes should be stopped, and long-term follow-up may be needed for patients treated with radiotherapy, chemotherapy, and teratogenic drugs such as retinoids. The journey of a thousand miles must begin with a single step.

References

1Slaughter DP, Southwick HW, Smejkal W. Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer 1953;6:963-8.
2Slaughter DP. Multicentric origin of intraoral carcinoma. Surgery 1946;20:133-46.
3Oijen MG, Slootweg PJ. Oral field cancerization: Carcinogen-induced independent events or micrometastatic deposits? Cancer Epidemiol Biomarkers Prev 2000;9:249-56.
4Kale AD, Mane DR, Babji D, Gupta K. Establishment of field change by expression of cytokeratins 8/18, 19, and MMP-9 in an apparently normal oral mucosa adjacent to squamous cell carcinoma: An immunohistochemical study. J Oral Maxillofac Pathol 2012;16:10-5.
5Tanaka T. Chemoprevention of oral carcinogenesis. Eur J Cancer B Oral Oncol 1995;31:3-15.
6Tanaka T. Effect of diet on human carcinogenesis. Crit Rev Oncol Hematol 1997;25:73-95.
7Tanaka T. Chemoprevention of human cancer: Biology and therapy. Crit Rev Oncol Hematol 1997;25:139-74.
8Braakhuis BJ, Tabor M, Kummer JA, Leemans CR, Brakenhoff R. A genetic explanation of Slaughter's concept of field cancerization: Evidence and clinical implications. Cancer Res 2003;63:1727-30.
9Warren S, Gates O. Multiple primary malignant tumors. A survey of the literature and a statistical study. Am J Cancer 1932;16:1358-414.
10Scholes 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.
11Jayam R. Oral field cancerization-A review. Journal of Indian Academy of Oral Medicine and Radiology 2010;22:201-5.
12Dakubo GD, Jakupciak JP, Birch-Machin MA, Parr RL. Clinical implications and utility of field cancerization. Cancer Cell Int 2007;7:2.
13Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2002;2:442-54.
14Friedl P, Wolf K. Tumour-cell invasion and migration: Diversity and escape mechanisms. Nat Rev Cancer 2003;3:362-74.
15Kakinuma T, Hwang ST. Chemokines, chemokine receptors, and cancer metastasis. J Leukoc Biol 2006;79:639-51.
16Warner KA, Miyazawa M, Cordeiro MM, Love WJ, Pinsky MS, Neiva KG, et al. Endothelial cells enhance tumor cell invasion through a crosstalk mediated by CXC chemokine signalling. Neoplasia 2008;10:131-9.
17Mignogna MD, Fedele S, Lo Russo L, Mignogna C, de Rosa G, Porter SR. Field cancerization in oral lichen planus. Eur J Surg Oncol 2007;33:383-9.
18van Oijen MG, Slootweg PJ. Oral field cancerization: Carcinogen-induced independent events or micrometastatic deposits? Cancer Epidemiol Biomarkers Prev 2000;9:249-56.
19Van Oijen MG, van de Craats JG, Slootweg PJ. p53overexpression in oral mucosa in relation to smoking. J Pathol 1999;187:469-74.
20Dabelsteen E, Mandel U, Clausen H. Cell surface carbohydrates are markers of differentiation in human oral epithelium. Crit Rev Oral Biol Med 1991;2:493-507.
21Bongers 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.
22Tanaka T, Tanaka M, Tanaka T. Oral carcinogenesis and oral cancer chemoprevention: A review. Patholog Res Int 2011;2011:431246.
23Kishore KS, Shenai KP, Chatra LK. Field cancerization- A case report. Journal of Indian Academy of Oral Medicine and Radiology 2006;18:124-8.
24Papadimitrakopoulou 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.
25Mayne ST. Beta-carotene, carotenoids, and disease prevention in humans. FASEB J 1996;10:690-701.
26Mukherjee B, Ghosh MK, Hossain CM. Anticancer potential of vitamin A and beta-carotene: Mechanistic approach. NSHM J Pharm Healthc Manage 2011;2:1-12.