REVIEW ARTICLE

Alok A et al: Oral Field Cancerization

Oral Field Cancerization: A Review

Abhijeet Alok1, Indra Deo Singh2, Sunil R Panat3,
Shivani Singh4, Mallika Kishore5
1- Senior Lecturer, Department of Oral Medicine and Radiology, Sarjug Dental Correspondence to:
College and Mata R Devi Dental Hospital, Darbhanga (Bihar), India Dr. Abhijeet Alok,
2- Associate Professor & Head, Department of Psychiatry, Sri Krishna Medical Department of Oral Medicine and Radiology, Sarjug Dental College
and Mata R Devi Dental Hospital, Laheriasarai, Darbhanga, Bihar,
College and Hospital, Muzaffarpur (Bihar), India
India.
3- Professor & Head, Department of Oral Medicine and Radiology, Institute of
Dental Sciences, Bareilly,(U.P),India Contact Us : [email protected]
4- Junior Lecturer, Institute of Dental Sciences, Bareilly, U.P, India. Submit Manuscript : [email protected]
www.ijdmr.com
5- MDS, Oral Medicine and Radiology, Shahjahanpur, U.P, India.

ABSTRACT
Patients with head and neck squamous cell carcinoma (HNSCC) often develop multiple (pre) malignant lesions. This
finding led to the field of the cancerization theory, which hypothesizes that the entire epithelial surface of upper
aerodigestive tract has an increased risk for development of (pre) malignant lesions, because of multiple genetic
abnormalities in the whole tissue region. Cancer begins with multiple cumulative epigenetic and genetic alterations that
sequentially transform a cell or group of cells in a particular organ. These early genetic events may lead to clonal
expansion of preneoplastic daughter cells in a particular tumor field. Subsequent genomic changes in some of these
cells drive them toward the malignant phenotype. These transformed cells are diagnosed histopathologically as cancers,
owing to changes in the cells morphology. An important clinical implication is that fields often remain after surgery of
the primary tumor and may lead to new cancers, designated presently by clinicians as “second primary tumor” or “local
recurrence,” depending on the exact site and time interval. Conceivably, a population of daughter cells with early
genetic changes (without histopathology) remains in the organ, demonstrating the concept of field cancerization.

KEYWORDS: Head and Neck Squamous Cell Carcinoma, Second Primary Tumor, Molecular Methods, Field
Cancerization, Upper Aerodigestive Tract……………………………………………………………………………….....

INTRODUCTION
number five on the list of the most prevalent
One of the most common malignancies in cancer types.4
humans is head and neck squamous cell The prognosis of squamous cell carcinoma
carcinoma (HNSCC). The average 5-year patients is adversely influenced by development
survival rate of HNSCC is one of the lowest of a new tumor. Squamous cell carcinoma may
among aggressive cancers and has not improved arise as a recurrence of an incompletely
during the last two decades.1 HNSCC develops resected index tumor or second primary tumor
in the mucosal lining of the oral cavity, larynx (SPT) or second field tumor (SFT).5 Depending
and pharynx. HNSCC comprises about 5% of on both the location of the first primary tumor
diagnosed cancer cases in developed countries.2 and the age of the patient the incidence rate of
Worldwide, there is a prevalence of SPT is 10-35%.6
approximately 20 HNSCC cases per 100,000
individuals per year.3 HNSCC is ranked at These findings led to the field of cancerization

How to cite this article:

Alok A, Singh ID, Panat SR, Singh S, Kishore M. Oral Field Cancerization:A Review. Int J Dent Med Res 2014;1(3):98-104.

Int J Dent Med Res | SEPT - OCT 2014 | VOL 1 | ISSUE 3 98

 REVIEW ARTICLE
Alok A et al: Oral Field Cancerization

theory given by Slaughter and colleagues

ORAL FIELD CANCERIZATION
(1953) which hypothesized that the entire
epithelial surface of the upper aero digestive The mucosal changes in the entire upper aero
tract (UADT) has an increased risk for the digestive tract (UADT) were generally
development of (pre)malignant lesions because considered to be the result of exposure to
of multiple genetic abnormalities in the whole carcinogens that caused multiple genetic
tissue region.7 The investigators examined abnormalities in the whole tissue region. The
pathology slides of 783 patients with HNSCC in occurrence of multiple tumors can be explained
an effort to understand the gross changes found by two competing hypotheses
in epithelia surrounding these tumors and
explain their clinical behavior. It was  Monoclonal theory in which single cell
discovered that all of the epithelium beyond the is transformed, and through the mucosal
boundaries of the tumor possessed histologic spread, give rise to multiple genetically
changes, and 88 out of 783 patients were found related tumors.
to have more than one independent area of  Polyclonal theory in which multiple
malignancy.8 At the time of study, there was no transforming events give rise to
molecular basis for the observation. However, genetically unrelated multiple tumors.
many investigators have since attempted to use  An alternative theory for the occurrence
recent molecular techniques to elucidate the of multiple malignant lesions has been
mechanism that underlies the clinical proposed and is based on the premise
phenomenon of field cancerization.9 that any transforming events is rare and
that multiple lesion arise due to
An accumulation of genetic alterations form the widespread migration of transformed
basis for progression from a normal cell to a cells through the whole aerodigestive
cancer cell, referred to as the process of tract.12
multistep carcinogenesis.7,9 Until now, the
number of genetic alterations is known to Two types of migration are involved in the
increase with the level of malignancy as judged concept of this theory: a) Migration of tumor
by histo-pathological examination. The process cells by for ex. Saliva (micro metastases) b)
of field cancerization can be defined in Intraepithelial migration of the progeny of the
molecular terms.10 Based on histological initially transformed cells.Information about all
examinations, field cancerization was described of the different theories can be gathered in two
as follows: (a) oral cancer develops in different types of investigations.13
multifocal areas of precancerous change, (b)
 To search for differences in alterations
histologically abnormal tissue surrounds the
between the histologic normal tumor
tumors, (c) oral cancer often consists of
adjacent mucosa (TAM) from smokers/
multiple independent lesions that sometimes
alcohol drinkers and normal TAM from
coalesce, and (d) the persistence of abnormal
non-smokers / non-drinkers. If there are
tissue after surgery may explain SPTs and local
migrating tumor cells, one expects them
recurrences.4,10 The terms “field effect” and
to be present in the TAM from smoking
field cancerization were used when
as well as non-smoking HNSCC. Thus
(pre)neoplastic processes at multiple sites were
TAM from smoking as well as non-
described, and it was often assumed that these
smoking HNSCC patients must exhibits
had developed independently.11
the same alterations. These alterations

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Alok A et al: Oral Field Cancerization

must be absent in smoking healthy to have elapsed between detection of the

individuals, as in those cases, there is no tumors. SPTs can be divided into two groups:
source for migrating tumor cells. synchronous SPTs, which develop
 Second way is to examine the clonality simultaneously with or within six months after
of the multiple (pre) malignant lesions. the index tumor, and metachronous SPTs,
This can be done by analysis of early which develop > six months after the initial
genetic alterations in the development of tumor. Most SPTs are metachronous and
HNSCC. The separate lesions will share develop during follow-up of HNSCC patients
common genetic alterations if they have after curative treatment of the first tumor.4,15
developed from a single clone. The
The term “SPT” was proposed to be allocated
clonal relationship between multiple
for the second tumor that has developed
lesions points to the migration of tumor
independently from the first tumor. When a
cells or progenitor cells.
second tumor arises from the same field in
which a first tumor has developed, it was
SECOND PRIMARY TUMOR preferred to designate it as a “second field
Despite advances in therapy long term survival tumor” (SFT).16
of head and neck cancer patients has not
significantly improved in the last 20 years. An DISTANT SECOND LESIONS
important reason for this lack of progress is the
Because of common pathway between the oral
development of secondary primary tumor in the
cavity, lungs and esophagus, there is a similar
upper aerodigestive tract. Patients at highest
exposure pathway to the mucosa from the
risk are those with early-stage disease, when
environmental carcinogens. Patients with
control of the first tumor, and therefore
HNSCC and concurrent esophageal squamous
survival, is greatest.14
cell lesions have been studied for the
For SPT, most clinicians currently use the relationship between these two tumors. One
criteria given by Warren and Gates,15 which study was conducted by Califano et al to study
were published in 1932: (a) each of the tumors clonal relationship in sixteen patients by the use
must present a definite picture of malignancy, of microsatellite markers. Result of the study
(b) each must be distinct, and (c) the probability showed that the lesions were not clonally
of one being a metastasis of the other must be related in the fourteen of patients. However two
excluded.4,15 Histological examination will of the sixteen patients had lesions that
often find that the tumor is malignant, but with demonstrated clonal relatedness, one migrating
this method, it is difficult to prove whether at a distance of 40 cm.17 Therefore it is
lesions are distinct. To exclude the possibility generally assumed that esophageal lesions in
of a local recurrence, most studies use a conjugation with HNSCC represent two
distance of at least 2 cm between the first tumor separate primary tumors rather than metastases.
and the SPT.11,15
Another study conducted by Leong et al
Another criteria for SPT, at the same or an examined the question of synchronous lung
anatomical adjacent sites, is that it should be tumors and their relationship to HNSCC.
classified by the time of recurrence. For a tumor Sixteen patients with HNSCC and a
to be considered a SPT, at least three years had concurrently solitary lung lesion were tested by
microsatellite analysis. 63% demonstrated

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Alok A et al: Oral Field Cancerization

concordant patterns of loss at all loci tested, radiography like CT, MRI and PET plays an
suggesting that the majority of the solitary lung important role in the detection of SPTs and
lesions were in fact metastases rather than metastatic lesions. David L Schwartz (2003)
separate primary tumors.18 performed extended field FDG-PET in 33
patients of stage II-IV squamous cell carcinoma
Therefore, the distance between two of oral cavity, esophagus or larynx. Of these
malignancies does not necessarily predict thirty three patients, seven had evidence of
clonality but distant, peripheral, solitary, distant lesions, four with metastasis and three
squamous lung lesions in conjunction with patients with synchronous primary cancers of
HNSCC are thought to be metastases and aerodigestive tract.22 Hence it was concluded
concurrent esophageal tumors are thought to be that FDG-PET is feasible for detection of SPT
separate primary tumors. While the probability and distant metastases. Similar reports were
of synchronous aerodigestive tract tumors also found in their study by Marx K Wax et al.
remains high with environmental exposure, the and Gerhard W Goerres et al.23,24
relationship between them is often predicted by
the anatomic subset rather than distance.19
THERAPEUTIC
MOLECULAR METHODS OF IMPLICATIONS FOR FIELD
DETERMINING CLONALITY CANCERIZATION
The idea of clonality has formed the basis for The controversy between lateral spread of
the way researchers view cancer and its clones versus multiple foci of independent
development. A single cell, altered by alterations does not currently affect the surgical
inactivation of a tumor suppressor gene(s) and medical management of these premalignant
and/or activation of an oncogene(s), will gain a and malignant lesions. However, detection and
growth advantage and expand to form a clonal therapy based on molecular techniques depend
mass of cells or tumor.20 on an answer to this question.
The underlying technique utilizes a few basic It is a well-known clinical experience that even
points namely identification of early, shared after surgical removal of a tumor, there is a high
genetic alterations that are unique to the lesions risk for another tumor to develop in the same
and are not found elsewhere in the normal anatomical area. In some cases, the new tumor
mucosa. Thus, these molecular patterns form a formation can be explained because of the
type of DNA fingerprint. An early cytogenetic growth of incompletely resected carcinoma.
technique used to determine clonality is However, for the cases where the tumor had
karyotype analysis. Another common method is been removed, a genetically altered field is the
the use of p53 mutations. p53 mutated gene has cause of new cancer.
been shown to be important in the regulation of
apoptosis and many other pathways.21 The presence of altered fields of mucosa
beyond the limits of resection has been shown
DETECTION OF SECOND both histologically and on a molecular basis.
PRIMARIES / METASTATIC Initial studies performed demonstrated that p53
LESIONS mutations noted in histologically normal
margins could be detected in those patients with
Despite the molecular methods, the specialized known mutations in altered margins.25 .

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The histological benign mucosa often can shown to up-regulate the retinoic acid receptor-
progress to further premalignant or malignant β, leading to a good clinical response in head
disease. Microsatellite alterations have been and neck pre-malignant lesions.28 High doses of
shown to be predictive of malignant 13 cis-retinoic acid led to a regression in
progression. In the future, the presence of leukoplakia as compared with placebo and also
altered clones at mucosal margins may be an lead to the prevention of second primary
indication for more aggressive therapy, tumors.29 However, an additional study noted
including chemopreventive or radiotherapy to that, despite clinical regression of pre-malignant
treat altered clonal patches that are unable to be lesions, genetic alterations in mucosal fields
detected grossly and are beyond the initial remain unchanged.30 This implies that definitive
scope of surgical excision. therapy for genetically altered fields of mucosa
will ultimately consist of targeted ablation of
Current management is often site-specific. altered clonal populations, repair of genetic
Recurrent oral premalignant disease is often damage in affected cells, or ongoing treatment
treated by surgical excision whereas diffused with chemopreventive agents that will continue
high grade premalignant changes in laryngeal for years or decades.
mucosa are frequently treated with
radiotherapy.
CONCLUSION
CHEMOPREVENTION While the focus of clinical trials for
chemoprevention agents has been on the use of
Whether they are clonally related or not, it is retinoid-based compounds but the toxicity of
clear that there are wide fields of mucosa that this drug (conjunctivitis, mucositis, dry skin,
undergo genetic alterations in patients. It is not hypertriglyceridemia, and malaise) at higher
feasible to remove all of the areas with doses may limit its utility.
molecular alterations surgically. Thus, using the
knowledge gained from molecular studies, Field cancerization is a well-known and well
researchers have attempted to come up with documented process of malignant
protective measures that could render the transformation. Several studies confirm the
mucosa less sensitive to DNA alterations. importance of this phenomenon in tumor
Patients at risk could be treated to prevent the development. The presence of field with
development of disease and patients with pre- genetically altered cells is a risk factor for
malignant lesions could have them reversed or cancer. The large number of pre-neoplastic cells
halted. And finally, chemoprevention could be in the proliferating fields is likely to increase
used to prevent the recurrence of cancer after the cancer risk dramatically. The finding that
surgery. field changes frequently in the tissue altered
mucosa of the HNSCC patients creates a
There have been several proposed compounds different view on tumor excision margins that
thought to be potential chemotherapeutic contain molecularly altered cells. Early
agents, but perhaps the most widely studied detection and monitoring of the field may have
compound has been 13 cis-retinoic acid.26 This profound implications for cancer prevention.
family of chemicals has shown to play a role in
the differentiation, development, and growth of
epithelial cells.27 13 cis-retinoic acid has been

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Conflict of Interest: Nil

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