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Better grade of tumor differentiation of oral squamous cell carcinoma arising

in background of oral submucous fibrosis

Article  in  Medical Hypotheses · July 2013

DOI: 10.1016/j.mehy.2013.07.001 · Source: PubMed

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 Medical Hypotheses 81 (2013) 540–543

Contents lists available at SciVerse ScienceDirect

Medical Hypotheses
journal homepage: www.elsevier.com/locate/mehy

Better grade of tumor differentiation of oral squamous cell carcinoma

arising in background of oral submucous fibrosis
Sachin C. Sarode ⇑, Gargi S. Sarode 1
Department of Oral Pathology and Microbiology, Dr. D.Y. Patil Dental College and Hospital, Dr. D.Y. Patil Vidyapeeth, Sant-Tukaram Nagar, Pimpri, Pune 18, Maharashtra, India

a r t i c l e i n f o a b s t r a c t

Article history: Oral submucous fibrosis (OSMF) is a potentially malignant disorder of the oral cavity. Most of the people
Received 21 May 2013 affected by OSMF are betel quid chewers. It is characterized by epithelial atrophy and progressive accu-
Accepted 2 July 2013 mulation of collagen fibers in lamina propria and submucosa of the oral mucosa. 7.6% of OSMF cases
undergo oral squamous cell carcinoma (OSCC) transformation of which majority display low grade of
tumor differentiation. In the present paper, a hypothesis has been proposed to correlate atrophy, turnover
rate and surface keratization in OSMF with degree of tumor differentiation in OSCC. A novel hypothesis
for epithelial atrophy in OSMF has also been emphasized.
High proliferative activity and basal cell hyperplasia in conjunction with rapid exfoliation of superficial
cells and epithelial atrophy suggest that epithelial turnover rate is very high in OSMF. Presence of surface
keratinized layer in this situation suggests faster maturation or differentiation of epithelium in OSMF.
Thus, the epithelial cells are genetically programmed for high turnover rate and faster differentiation
or maturation to form keratin. During malignant transformation of OSMF, the transformed epithelial cells
may retain the genetic memory of faster differentiation and maturation resulting in better grade of tumor
differentiation. The well differentiated OSCC has good prognosis, better survival rate and less chances of
recurrence of regional and distant metastasis. Studies are needed to explore the biomarkers or molecular
markers associated with carcinogenesis like genetic instability, oncogenes, tumor suppressor genes and
angiogenesis in OSCC associated with OSMF. If investigated in the suggested direction, it might provide
some important clues about the pathogenesis of OSCC arising in background of OSMF and for the future
development of treatment strategies.
Ó 2013 Elsevier Ltd. All rights reserved.

Introduction with oropharyngeal cancer and the tumor is known to have a

Oral cancer is the most common cancer affecting the Indian
males (13% of all the malignancies) and is the third most common
cancer diagnosed in the Indian females. Over 1,000,000 new cases
of oral squamous cell carcinoma (OSCC) are registered every year
in India [1]. Tobacco, alcohol, areca nut, and human papilloma
virus are some of the well-established common etiologic factors
of OSCC. Each of these etiologic agents follows a unique model of
oral carcinogenesis involving different molecular mechanisms.
There are distinct patterns of disease presentation depending on
the etiologic agent. For example, tongue cancer is more common
among smokers, whereas buccal mucosa is the most common site
for cancer among smokeless tobacco users [2,3]. Alcohol is typi-
cally associated with a relatively higher incidence of cancer of
the tongue and floor of mouth [4,5]. HPV is strongly associated
⇑ Corresponding author. Tel.: +91 9922491465.
E-mail addresses: drsachinsarode@gmail.com (S.C. Sarode), gargi14@gmail.com
(G.S. Sarode).
1
Tel.: +91 9823871462.
distinct clinical behavior, histopathologic characteristics, and
treatment response [6].
Areca nut chewing is a unique problem in the Indian subconti-
nent. Areca nut is an independent group 1 human carcinogen in
accord with the International Agency for Research on Cancer,
World Health Organization with respect to its monographs of
1985 and 2004 [7,8]. However, only areca nut chewing may not
cause any oral pathology as such [9], but along with the slaked
lime and other ingredients (which can cause inflammation) it leads
to a ubiquitous oral potentially malignant disorder (OPMD) called
oral submucous fibrosis (OSMF) which is characterized by progres-
sive fibrosis of the oral mucosa [9,10]. In an epidemiological study
on oral cancer and OPMDs in a rural Indian population, the malig-
nant transformation rate of OSMF was 7.6% (5 of 66) over a 17-year
period (median observation, 10 years) [11]. OSCC associated with
OSMF is one of the most common malignancies in South and
Southeast Asian countries [12].
Histopathologic evaluation of the degree to which these tumors
resemble their parent tissue (squamous epithelium) and produce
their normal product (keratin) is called grading. OSCC is graded

0306-9877/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.mehy.2013.07.001
 S.C. Sarode, G.S. Sarode / Medical Hypotheses 81 (2013) 540–543
on a three-point (grades I–III) or a four-point (grades I–IV) scale.
The less differentiated tumors receive higher points. The histopath-
ologic grade of a tumor is related somewhat to its biologic behav-
ior. In other words, a tumor that is mature enough to closely
resemble its tissue of origin seems to grow at a slightly slower pace
and metastasize later in its course. Such a tumor is called low-
grade, grade I or well-differentiated OSCC. In contrast, a tumor with
more cellular and nuclear pleomorphism and little or no keratin
production may be so immature that it becomes difficult to iden-
tify the tissue of origin. Such a tumor often enlarges rapidly, metas-
tasizes early in its course and is termed as high-grade, grade III/IV,
poorly differentiated or anaplastic. A tumor with a microscopic
appearance somewhere between these two extremes is labeled
as ‘‘moderately differentiated’’ carcinoma [13].
Personal observation
We observed that patients with OSCC along with OSMF are
pathologically different from patients with OSCC without OSMF.
It is found that patients with OSCC with OSMF show better grade
of tumor differentiation. In our observation of 381 OSCC cases,
34 OSCC cases (8.92%) were associated with OSMF, out of which
30 (88.23%) cases showed better grade of tumor differentiation
(well differentiated). A study by Zhou et al. [14] reported a similar
observation of having a higher proportion of well-differentiated tu-
mors in patients with OSMF. Recently, Chaturvedi et al. [15] in
their study of 112 OSCC cases with OSMF reported 20.5% of well
differentiated, 66.1% of moderately differentiated, and 13.4% of
poorly differentiated tumors.
Hypothesis
Personal observation coupled with results of two previous stud-
ies [14,15] led us to hypothesize that OSCC arising in background
of OSMF shows better grade of tumor differentiation. Genetic
memory associated with epithelial biology in OSMF is carried for-
ward during malignant transformation which is responsible for a
better grade of tumor differentiation.
Why grade of tumor differentiation is better for OSCC arising in
background of OSMF?
It is well known fact that, OSMF is characterized by epithelial
atrophy for which various reasons are proposed in the literature.
This conspicuous epithelial atrophy is evident by reduced thick-
ness and number of cell layers which can be quantified at micro-
scopic level using image analyzing software. It is reported that
proliferative activity of epithelium is high in OSMF [16]. Moreover;
we observed basal cell hyperplasia in majority of our OSMF cases
(Fig. 1). These activities ideally should cause epithelial hyperplasia
instead of atrophy.
Proposal for epithelial atrophy in OSMF
Many pathogenesis have been already proposed for epithelial
atrophy in OSMF, but none has been proved on scientific grounds.
Despite many efforts, the reason still remains unsubstantiated. We
hereby propose a novel hypothesis for epithelial atrophy in OSMF
(Fig. 2).
Minor salivary glands (MSGs) are major source of membrane
associated mucin (MAM) especially at their local areas [17]. The
MAM attaches to the ‘microplicae’ (ridge like folds present on the
surface of superficial cells of oral epithelium) with the help of
membrane anchored ‘mucous binding proteins’ [18–20]. This
MAM then acts as a scaffold for the formation of highly hydrated
541
Fig. 1. Photomicrograph showing atrophic epithelium of oral submucous fibrosis
with basal cell hyperplasia (white arrow) and surface parakeratinised layer (black
arrow). (HE stain; X400).
and viscous gel called salivary mucous gel (SMG) [21]. In addition,
lactoperoxidase [22] and trefoil factor 3 [23] may be identified in
the formation of SMG. This SMG protects the superficial cells of
oral epithelium from normal physiologic frictions of the oral cavity.
We also believe that SMG, through its function as lubrication, also
prevents the early exfoliation of the superficial cells and thus
maintains the thickness and integrity of oral epithelium (Fig. 2).
In OSMF, involvement of MSG has been reported in the litera-
ture [24]. This causes less secretion of saliva at the local area by
MSG leading to less availability and expression of MAM on the tips
of microplicae. This prevents the formation of SMG and subse-
quently leads to less protection and lubrication for superficial cells
of the oral epithelium. This will lead to rapid exfoliation of super-
ficial cells even by normal physiologic friction leading to atrophic
oral epithelium. This phenomenon explains the reason for atrophic
epithelium even in the presence of proliferative activity and basal
cell hyperplasia. The atrophic epithelium in association with high
turn rate makes it susceptible to carcinogenic attack. Hence, OSMF
is considered as OPMD under the category of ‘morphologically al-
tered tissue in which external factor is responsible for the etiology
and malignant transformation’ [25,26].
Rapid exfoliation and better grade of differentiation of OSCC
High proliferative activity and basal cell hyperplasia in conjunc-
tion with rapid exfoliation of superficial cells and epithelial atro-
phy suggest that epithelial turnover rate is very high in OSMF.
We observed that superficial cells in OSMF are always keratinized
(differentiated) (Fig. 2). This means that maturation or differentia-
tion of epithelium is very fast in OSMF. Thus, the epithelial cells are
genetically programmed for high turnover rate and faster differen-
tiation or maturation to form keratin. This genetic re-adaptation
for altered situation may be necessary to fulfill the functional
requirement and protection of underlying cell layers. We believe
that during malignant transformation of OSMF, the transformed
epithelial cells may retain the genetic memory of faster differenti-
ation and maturation. And hence the OSCC arising in background of
OSMF is better differentiated (Fig. 2).
Importance
The importance of the hypothesis is that if investigated, it might
provide some important clues about the pathogenesis of OSCC
arising in the background of OSMF and better grade of tumor
542 S.C. Sarode, G.S. Sarode / Medical Hypotheses 81 (2013) 540–543
Fig. 2. Hypothesis for better grade of tumor differentiation of oral squamous cell carcinoma arising in background of oral submucous fibrosis.
differentiation. The well differentiated tumor lacks anaplasticity,
which in turn indicates less rapid growth, less chances of cervical
metastasis, fewer chances of post-operative recurrence, better
prognosis and survival rate. Hence, it will help for the future devel-
opment of treatment strategies.
Evaluation of the hypothesis and how to test it
Studies on patho-physiology of oral epithelium in OSMF with
emphasis on cell turn over rate, proliferative activity, expression
of mucous binding protein, structure of microplicae and detailed
analysis of mucin will help in strengthening the proposed hypoth-
esis. The epithelial turnover rate can be studied with the help of
proliferative markers (Ki67, PCNA, AgNOR etc) and measurement
of the S phase fraction using DNA synthesis precursors such as
tritiated thymidine. OSMF is a generalized condition of the oral
cavity. The surgical margins of OSCC associated with OSMF also
show the features of OSMF and hence aforementioned studies on
surgical margins will further help in validation of the proposed
hypothesis.
Studies are needed to explore the biomarkers or molecular
markers associated with carcinogenesis in OSCC associated with
OSMF. This can involve studies on genetic instability, oncogenes,
tumor suppressor genes and angiogenesis. Areas of chromosome
frequently lost in OSCC include 3p, 4q, 5q21-22, 8p21-23, 9p21-
22, 11q13, 11q23, 13q, 14q, 17p, 18q and 22q. Oncogenes are
broadly represented by growth factors or growth factor receptors
(hst-1, int-2, EGFR/erbB, cerbB-2/Her-2, sis), intracellular signal
transducers (ras, raf, stat-3), transcription factors (myc, fos, jun,
c-myb), cell cycle regulators (Cyclin D1) and those involved in
apoptosis (bcl-2, Bax). Tumor suppressor genes implicated in OSCC
include p53, p16, p21 and p27. The angiogenesis initiating signals
are exemplified by vascular endothelial growth factor (VEGF),
interleukin-8 (IL-8) and acidic and basic fibroblast growth factors
(FGF 1/2). The proto-typical angiogenesis inhibitor is thrombo-
spondin-1, which binds to CD36, a transmembrane receptor on
endothelial cells. Also expression of VEGF family members, i.e.
VEGF-A and VEGF-C in OSCC has been reported.
Study of all the aforementioned molecular markers will help in
understanding the carcinogenesis in OSCC associated with OSMF.
Conflict of interest statement
None.
Source of finding
None.
 S.C. Sarode, G.S. Sarode / Medical Hypotheses 81 (2013) 540–543 543

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