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 Table of Contents  
REVIEW ARTICLE
Year : 2019  |  Volume : 9  |  Issue : 1  |  Page : 28-35

Oral field cancerization: Tracking the invisible


1 Department of Oral Pathology, CODS, Davangere, Karnataka, India
2 Department of Microbiology, CODS, Davangere, Karnataka, India

Date of Web Publication17-May-2019

Correspondence Address:
Dr. Harsha Mallegowda
Senior lecturer, Department of Oral Pathology, KLR'S Lenora Institute of Dental Sciences, Rajahmahendravaram, Andhra Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijohs.ijohs_34_18

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  Abstract 


Cancer is one of the most common diseases affecting humans worldwide, despite latest advances made in molecular and cell biology, how cancer cells progress through carcinogenesis and acquire their metastatic ability is still questionable. Oral cavity is one of the commonest site for potentially malignant disorders. These pre-malignant pathologies may progress to dysplastic lesions then to invasive carcinomas.The presence of one or more mucosal areas consisting of epithelial cells that have cancer-associated genetic or epigenetic alterations.The prognosis of squamous cell carcinoma patients is adversely influenced by development of a new tumor. This review highlights the pathophysiological changes during field cancerization

Keywords: Carcinoma, field cancerization, second field


How to cite this article:
Mallegowda H, Theresa R, Amberkar VS. Oral field cancerization: Tracking the invisible. Int J Oral Health Sci 2019;9:28-35

How to cite this URL:
Mallegowda H, Theresa R, Amberkar VS. Oral field cancerization: Tracking the invisible. Int J Oral Health Sci [serial online] 2019 [cited 2019 Aug 20];9:28-35. Available from: http://www.ijohsjournal.org/text.asp?2019/9/1/28/258571



Cancer is one of the most common diseases affecting humans world wide. Despite the latest advances made in molecular and cell biology, how cancer cells progress through carcinogenesis and acquire their metastatic ability is still questionable. The oral cavity is one of the most common sites for potentially malignant disorders. These premalignant pathologies may progress to dysplastic lesions then to invasive carcinomas.


  Oral Cancer Top


  1. One of the most widespread malignancies in humans
  2. Comprises about 5% of diagnosed cancer cases in the developed countries [1]
  3. The average 5-year survival rate of HNSCC is one of the lowest among aggressive cancers [1]
  4. Worldwide, there is a prevalence of approximately 20 head-and-neck squamous cell carcinoma (HNSCC) cases per 100,000 individuals per year [1]
  5. HNSCC is ranked at no. 5 on the list of the most prevalent cancer types
  6. The prognosis of squamous cell carcinoma patients is adversely influenced by the development of a new tumor.



  Oral Field Cancerization Top


Definition

Previous

”Increased risk of cancer development in the entire upper aerodigestive tract due to multiple genetic abnormalities, in the whole region after prolonged exposure to carcinogen.[2]

Present

The presence of one or more mucosal areas consists of epithelial cells that have cancer-associated genetic or epigenetic alterations.[3]


  History Top


The development of locally recurrent cancer and the second primary tumors has frequently been explained by the concept of “field cancerization.”[4] (Slaughter et al. 1953) used the term field cancerization for the first time.[4]

Field cancerization was described as follows:[4]

  1. Oral cancer develops in the multifocal areas of precancerous change
  2. Histologically abnormal tissue surrounds the tumor
  3. Oral cancer often consists of multiple independent lesions that sometimes coalesce
  4. The persistence of abnormal tissue after surgery may explain second primary tumors and local recurrences.


The terms “field effect” and field cancerization were used when (pre) neoplastic processes at multiple sites were described, and it was often assumed that these had developed independently.[5]

”Cancer does not arise as an isolated cellular phenomenon but rather as an anaplastic tendency involving many cells at once.”[5]

  • Field cancerization was first described in oral cancers
  • Molecular genetic studies conducted in the head-and-neck tumors to explain the mechanisms and importance of this phenomenon.[5]


The term “lateral cancerization” was subsequently used. It indicates that the lateral spread of tumors was due to the progressive transformation of cells adjacent to a tumor rather than the spread and destruction of the adjacent epithelium by preexisting cancer cells.[5] Chronic exposure to tobacco carcinogens in the upper aerodigestive tract causes genetic and epigenetic damage in epithelial cells is explained in [Figure 1].
Figure 1: Chronic exposure to tobacco carcinogens in the upper aerodigestive tract causes genetic and epigenetic damage in epithelial cells

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The concept has been challenged because some clinically diagnosed second primary tumors distant from the original tumor appeared to derive from the clonal spreading of the original one based on genetic analysis (Bedi et al., 1996).[6]

Clonal spreading occurred in invasive and noninvasive lesions although the probability of clonal spreading increased with tumor progression. Other multiple oral lesions developed independently, supporting a strong role for field cancerization (Jang et al., 2001).[6] Accumulation of this damage leads to the development of premalignant lesions and invasive cancers. Field cancerization and local relapse is shown in [Figure 3].
Figure 2: Tumor heterogeneity. A; Genetic /epigeneticclonall evolution, B: Environmentally determined effects on cancer cell properties,C: Cancer stem cell model, D: Cancers in which heterogeneity is determined by cancer stem cell differentiation, clonal evolution & environmental effects

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Figure 3: Field cancerization and local relapse. The relationship between field cancerization and types of relapse is shown. A precursor field (or field; shown in light blue) is monoclonal in origin and does not show invasive growth or metastatic behavior, which is the hallmarks of an invasive carcinoma

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Oral field cancerization is probably a general phenomenon of epithelial tumors.[5] An important physiologic function of epithelia is their protective role that inevitably exposes them to environmental substances, including carcinogens that can create a vast area of genetically altered cancer fields.[5] Epithelial cells frequently self-renew and can undergo abnormal proliferation. Hyperplastic epithelia could form the basis of neoplastic transformation leading to the formation of the most common types of cancers of the human body.[5],[6]

Like most cancers, HNSCCs are not simply an aggregate of a genetically identical cell population but are composed of cells with marked genetic and cellular heterogeneity.

This unexpectedly high degree of heterogeneity is thought to result from a combination of genomic instability and clonal evolution.[7]

Tumor heterogeneity

Heterogeneity can arise within tumors through as follows:[7]

  1. The stochastic process of clonal evolution
  2. Extrinsic environmental differences within tumors
  3. The presence of cancer stem cells th'at variably differentiate
  4. Combination.


Chronic exposure to tobacco carcinogens in the upper aerodigestive tract causes genetic and epigenetic damage in epithelial cells explained in [Figure 2]

Carcinogenesis model

  1. The development of a field with genetically altered cells plays a central role
  2. This preneoplastic field is of monoclonal origin and expands noninvasively superseding normal epithelium
  3. Clonal divergence and selection within the field ultimately lead to the development of cancer
  4. These fields can be large (>7 cm diameter) and are often not visible for the surgeon explaining that they may remain after resection of the primary tumor [8]
  5. When not removed, a field is an important risk factor for secondary cancer.


This model is well explained in [Figure 11], emphasising the level of detection and carcinogenesis progression.

Local and distant recurrences of tumors are shown in [Figure 4][9]
Figure 4: Local and distant recurrences. Local (blue) and distant (green) premalignant fields give rise to second field tumors and second primary tumors (both red), respectively

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The criteria used to diagnose multiple primary carcinomas as originally described by Warren and Gates and modified by Hong were as follows:[10]

  1. Each neoplasm must be anatomically separate and distinct (if the intervening mucosa demonstrates dysplasia, it is considered a multicentric primary neoplasm)
  2. 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.


Proposed molecular diagnostic and therapeutic procedures after surgery of head-and-neck squamous cell carcinoma explained in [Table 2].
Table 1: Markers in the determination of oral field cancerization

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Table 2: Proposed molecular diagnostic and therapeutic procedures after surgery of head-and-neck squamous cell carcinoma

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The principle of oral field cancerization

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. These tissues can give rise to potentially malignant and malignant lesions.

Theories of field cancerization

Field cancerization include two main theories based on clonality.


  Clonal Theory Top


  1. Polyclonal theory
  2. Monoclonality theory.


Polyclonal theory

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.[8]

  1. Tumor-associated mucosa margins associated with smoking harbor altered cells
  2. Field changes such as increase in the nuclear area, proliferation, and p53 mutation, but these changes are seen in tumor-free smokers
  3. Epidemiologically, the risk of developing single primary tumors (SPTs) is higher in smokers/drinkers compared with nonsmokers/drinkers
  4. The risk of development of SPT decreases when the patient quits smoking and alcohol.


Common clonal origin in MPTs and is based on the similarity of genetic changes. Schematic representation of polyclonality theory shown in [Figure 5]
Figure 5: Schematic representation of polyclonality theory

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  Monoclonal Theory Top


The molecular events occur in a single progenitor with widespread expansion or lateral spread across the mucosa; two types of migration have been explained as follows:

  1. Migration of tumor cells through saliva – micrometastasis
  2. Intraepithelial migration of the progeny of the initially transformed cells.


Schematic representation of monoclonality theory shown in [Figure 6]
Figure 6: Schematic representation of monoclonality theory (a) micrometastasis of tumor cells and (b) intraepithelial migration of tumor cells

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Preneoplastic feld is monoclonal in origin and does not show invasive growth or metastatic behaviour well explained in [Figure 8].[11]
Figure 7: Alterations in epithelium and stroma

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Figure 8: Field cancerization consists of one or more mucosal areas consisting of epithelial cells that have cancer-associated genetic or epigenetic alterations. A preneoplastic field (shown in light pink) is monoclonal in origin and does not show invasive growth or metastatic behavior, which is the hallmarks of an invasive carcinoma (dark pink)

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Common clonal origin in MPTs and is based on the similarity of genetic changes.[8]

Three theories have tried to explain the same as follows:

  1. Single cell/small clusters of cells migrate through submucosa
  2. The cells are shed in the lumen of an organ at one place and regrow at another
  3. The genetically altered field exists in the epithelium from which multiple clonally related neoplastic lesions develop which help in the lateral clonal spread of cancer and subsequent occurrence of new primaries.


Alterations in as follows:

  1. Epithelium
  2. Stroma.


The pathomechanisms of local tumor spread and relapse formation types include as follows:[12]

  1. In situ recurrences that arise in the residual organ/organ system not involved in the surgery for the primary tumor
  2. Scar recurrences that develop at the site of previous tumor resection.


Whereas field cancerization, the monoclonal or multiclonal displacement of normal epithelium by a genetically altered but microscopically undistinguishable homolog may explain the origin of in situ recurrences.

Oral field cancerization

  1. Describes clinically occult multifocal preneoplastic lesions of the epithelium within an anatomic region exposed to the same carcinogen(s) (e.g., cigarette smoking and human papillomavirus infection)[12]
  2. These lesions may not be apparent at histopathologic investigation but can be detected with molecular analyses for phenotypic or genetic alterations associated with carcinogenesis such as p53 gene mutations, integrated viral DNA, loss of heterozygosity, and microsatellite instability
  3. Both monoclonal and polyclonal lesions have been shown in those fields with genetically altered cells by X-chromosome inactivation analysis and comparison of distinct gene mutations
  4. Polyclonality is explained by multiple genetic lesions produced independently from each other by the same carcinogenic local environment
  5. Monoclonal fields result from the lateral expansion of a “patch” formed by a genetically altered stem cell exhibiting a significant growth advantage over the neighboring stem cells
  6. Cohesive lateral migration of these cells gradually displaces the normal epithelium. After the complete resection of carcinoma preserving part of the organ in which it developed, microscopically normal but genetically altered epithelium may remain in situ and acquire additional mutations or epigenetic alterations that can initiate the development of a second tumor of the same or a different histologic type, representing an in situ recurrence refer [Figure 13]
  7. If the resection margin of the tumor operation is located within this genetically altered epithelium, a scar recurrence could also be a consequence of field cancerization.[12]


Alterations in epithelium and stroma is explained in [Figure 7].

Field precancerization in relation to oral squamous cell carcinoma

  1. Most oral squamous cell carcinomas develop in fields of precancerized epithelium in which there is clonal expansion of phenotypically normal but genetically altered keratinocytes
  2. These genetically unstable precancerous keratinocytes manifest aneuploidy, gain or loss of chromosomal material, or alterations in the sequences of nucleotides
  3. The genomic instability favors further acquisition of genetic alterations leading to the growth of superiority or inferiority of the affected cells
  4. The genetically advantaged cells may ultimately acquire a cancerous phenotype.[13]


Schematic presentation of feld precancerization in relation to oral squamous cell carcinomas explained in [Figure 9].
Figure 9: Schematic presentation of field precancerization in relation to oral squamous cell carcinomas

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  Epigenetic Field for Cancerization Top


Epigenetic alterations are present not only in cancer cells but also in noncancerous tissues. Accumulation levels of aberrant DNA methylation in noncancerous tissues can correlate with the risk of cancer development, especially in chronic inflammation-associated cancers DNA methylation refer [Figure 10]. The close correlation in noncancerous tissues was prominent for epigenetic alterations, compared with genetic alterations, and formed a concept of “epigenetic field for cancerization (epigenetic field defect).” The epigenetic field defect has its unique characteristics, such as ease of measurement and reversibility, and harbors a rich chance of clinical translations.[14] Markers in the determination of oral feld cancerization are shown in [Table 1].[15]
Figure 10: (a) DNA methylation. (b) DNA methylation

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Figure 11: Carcinogenesis model

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  DNA Methylation Top


DNA methylation is an epigenetic alteration, involved in human cancers. DNA methylation has been proposed as a candidate mediator of this field cancerization. Methylation of MGMT, APC, TIMP3, RAR, ECAD, and p16 was detected in 38%, 33%, 61%, 67%, 29%, and 49% of tumors, respectively. Some of the patients who delivered methylation-positive tumor samples had also methylation-positive adjacent normal tissues. The epigenetic modifications represented by DNA methylation in the adjacent normal tissue in the course of HNSCC point to the usefulness of DNA methylation as a marker of epigenetic cancerization field and of the future risk of cancer development.[16]

The new classification is based on molecular information on the relationship between the first and secondary tumors. LR, local recurrence; SFT, second field tumor; SPT, second primary tumor refer [Figure 12].[17]
Figure 12: New classification of secondary cancer after removal of a primary head-and-neck squamous cell carcinoma

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  Summary Top


  1. The presence of a field with genetically altered cells is a risk factor for cancer
  2. The large number of preneoplastic cells in the proliferating fields is likely to increase cancer risk dramatically
  3. The early genetic events might lead to clonal expansion of premalignant daughter cells in a particular tumor field
  4. Subsequent genomic changes in some of these cells drive them toward the malignant phenotype. A population of daughter cells with early genetic changes (without histological changes) remains in the organ, demonstrating the concept of field cancerization
  5. For early detection of a cancer, one can rely on tumor markers
  6. Identification of molecular signatures in the genetically transformed but histologically normal cells (peritumoral cancer field)
  7. 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 refer [Figure 14].
Figure 13: Potential intermediate endpoint markers that aid in the detection of field change

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Figure 14: Diagnosis and treatment plan

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The presence of a field with genetically altered cells is a risk factor for cancer.

  • Oral pathologist in this field has a strong potential role to reveal new diagnostic markers for the early detection, modalities to prevent progression, and finally, ways to combat the development of the second primary tumor
  • Finally, not only early detection and management of oral cancer are important but also equally important are early identification and management of a field to have profound implications on cancer prevention and outcome of the treatment.



  Conclusion Top


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 HNSCC is around 20%. Early identification and management of field change is a vital determinant for prevention of cancer mortality and morbidity.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Alok A, Singh ID, Panat RS, Singh S, Kishore M. Cone beam computed tomography: A third eye for dental surgeon. IJDMR 2014;1:144-8.  Back to cited text no. 1
    
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Slaughter DP. Multicentric origin of intraoral carcinoma. Surgery 1946;20:133-46.  Back to cited text no. 2
    
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Braakhuis BJ, Tabor MP, Kummer JA, Leemans CR, Brakenhoff RH. A genetic explanation of slaughter's concept of field cancerization: Evidence and clinical implications. Cancer Res 2003;63:1727-30.  Back to cited text no. 3
    
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Braakhuis BJ, Leemans CR, Brakenhoff RH. Expanding fields of genetically altered cells in head and neck squamous carcinogenesis. Semin Cancer Biol 2005;15:113-20.  Back to cited text no. 4
    
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Dakubo GD, Jakupciak JP, Birch-Machin MA, Parr RL. Clinical implications and utility of field cancerization. Cancer Cell Int 2007;7:2.  Back to cited text no. 5
    
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Mao L, Hong WK, Papadimitrakopoulou VA. Focus on head and neck cancer. Cancer Cell 2004;5:311-6.  Back to cited text no. 6
    
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Magee JA, Piskounova E, Morrison SJ. Cancer stem cells: Impact, heterogeneity, and uncertainty. Cancer Cell 2012;21:283-96.  Back to cited text no. 7
    
8.
Ashwini BK, Sharada P, Hema KN, Chitra SM. Oral field cancerization: An update of evidences. J Dr NTR Univ Health Sci 2015;4:141-4.  Back to cited text no. 8
    
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Aparna M, Shenai P, Chatra L, Veena KM, Rao PK, Prabhu RV, et al. Field cancerization: A review. Arch Med Health Sci 2013;1:136-9.  Back to cited text no. 9
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Foo J, Leder K, Ryser MD. Multifocality and recurrence risk: A quantitative model of field cancerization. J Theor Biol 2014;355:170-84.  Back to cited text no. 10
    
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Leemans CR, Braakhuis BJ, Brakenhoff RH. The molecular biology of head and neck cancer. Nat Rev Cancer 2011;11:9-22.  Back to cited text no. 11
    
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Höckel M, Dornhöfer N. The hydra phenomenon of cancer: Why tumors recur locally after microscopically complete resection. Cancer Res 2005;65:2997-3002.  Back to cited text no. 12
    
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Feller LL, Khammissa RR, Kramer BB, Lemmer JJ. Oral squamous cell carcinoma in relation to field precancerisation: Pathobiology. Cancer Cell Int 2013;13:31.  Back to cited text no. 13
    
14.
Ushijima T. Epigenetic field for cancerization: Its cause and clinical implications. BMC Proc 2013;7 Suppl 2:K22.  Back to cited text no. 14
    
15.
Strzelczyk JK, Krakowczyk Ł, Płachetka A, Izdebska-Straszak G, Wiczkowski A. DNA methylation in tumor-adjacent normal tissue in the course of head and neck squamous cell carcinoma as an epigenetic field for cancerization. Hered Cancer Clin Pract 2012;10 Suppl 3:A20.  Back to cited text no. 15
    
16.
Mohan M, Jagannathan N. Oral field cancerization: An update on current concepts. Oncol Rev 2014;8:244.  Back to cited text no. 16
    
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Braakhuis BJ, Brakenhoff RH, Leemans CR. Second field tumors: A new opportunity for cancer prevention? Oncologist 2005;10:493-500.  Back to cited text no. 17
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11], [Figure 12], [Figure 13], [Figure 14]
 
 
    Tables

  [Table 1], [Table 2]



 

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  In this article
   Abstract
  Oral Cancer
   Oral Field Cance...
  History
  Clonal Theory
  Monoclonal Theory
   Epigenetic Field...
  DNA Methylation
  Summary
  Conclusion
   References
   Article Figures
   Article Tables

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