Hindawi Publishing Corporation

Journal of Oral Oncology

Volume 2013, Article ID 519312, 13 pages
http://dx.doi.org/10.1155/2013/519312

Review Article
The Outline of Prognosis and New Advances in Diagnosis of
Oral Squamous Cell Carcinoma (OSCC): Review of the Literature

Esam Ahmad Omar

Taibah University, P.O. Box 40361, Almadinah 41499, Saudi Arabia

Correspondence should be addressed to Esam Ahmad Omar; [email protected]

Received 7 May 2013; Accepted 12 July 2013

Academic Editor: Shun-Fa Yang

Copyright © 2013 Esam Ahmad Omar. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Objective. Oral squamous cell carcinoma (OSCC) has a remarkable incidence over the world and a fairly strenuous prognosis,
encouraging further research on the prognostic factors and new techniques for diagnosis that might modify disease outcome. Data
Sources. A web-based search for all types of articles published was initiated using Medline/Pub Med, with the key words such as oral
cancer, prognostic factors of oral cancer, diagnostic method of oral cancer, and imaging techniques for diagnosis of oral cancer. The
search was restricted to articles published in English, with no publication date restriction (last update April, 2013). Review Methods.
In this paper, I approach the factors of prognosis of OSCC and the new advances in diagnostic technologies as well. I also reviewed
available studies of the tissue fluorescence spectroscopy and other noninvasive diagnostic aids for OSCC. Results. The outcome is
greatly influenced by the stage of the disease (especially TNM). Prognosis also depends or varies with tumour primary site, nodal
involvement, tumour thickness, and the status of the surgical margins. Conclusion. Tumour diameter is not the most accurate when
compared to tumour thickness or depth of invasion, which can be related directly to prognosis. There is a wide agreement on using
ultrasound guided fine needle aspiration biopsies in the evaluation of lymph node metastasis.

1. Introduction rates have overall increased since the mid-1970s, with most
of this increase occurring since the late 1980s for both sexes.
Head and neck malignancies constitute approximately 5% European incidence rates have increased by 25% and 28% for
of all malignant tumors of the body [1]. Squamous cell men and women, respectively, in the last decade particularly
carcinoma represents almost 95% of the head and neck in years between 1998–2000 and 2007–2009. The mortality
cancers. The incidence of oral cancer varies from region to of oral carcinoma varies widely between African-Americans
another in the world. The most common oral sites involved and Caucasians and the ethnicity type may play a role in
vary as well from region to another. It appears that the the survival rates. The overall survival of patients has not
geographic location has no role with this rather than it improved significantly during the past 20 years, with 5-year
is the oral habits popular in certain countries which vary survival rates between 45–50%.
from region to another. In certain countries, such as Sri
Lanka, India, Pakistan, and Bangladesh, oral cancer is the Etiology
most common type of malignancy. In India oral cancer
represent more than 50% of all malignancy reported. The (i) Cigarette smoking: compared with persons who
high incidence rate in these countries may relate to specific do not smoke, the risk of oral cancer in persons
oral habits such as Betel and similar habits. Approximatively who smoke low/medium-tar cigarettes and high-tar
30–35% of the tumors (OSCC) occur a tongue, 20–25% at cigarettes was 8.5- and 16.4-fold greater, respectively
the gum, 5–7% at the floor of the mouth, 4–6% at the soft [3].
palate and only 2-3% at the cheeks [2]. The tumors were (ii) Alcoholic beverages may contain carcinogens or
usually diagnosed at the ages between 50 and 79 years, 96,6% procarcinogens, including nitrosamine and urethane
being over 40 years old. Generally, Oral cancer incidence contaminants and ethanol. Ethanol is metabolized
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2 Journal of Oral Oncology

by alcohol dehydrogenase and, to some extent, by Precancerous Lesions

cytochrome P450 to acetaldehyde, which may be
carcinogenic [3]. (i) Leukoplakia.
(ii) Erythroplakia.
(iii) Betel and similar habits [4]: the betel quid contains a
variety of ingredients, including betel vine leaf, betel (iii) Oral submucous fibrosis.
(areca) nut, catechu, and, often, slaked lime together (iv) Oral lichen planus.
with tobacco. Some persons chew the nut only, and (v) Chronic hyperplastic candidiasis (candida leuko-
others prefer paan, which includes tobacco and some- plakia).
times lime and catechu. In 1986, the International
Agency for Research on Cancer has deemed betel- (vi) Syphilis.
quid chewing an important risk factor, and the areca (vii) Actinic keratosis.
(betel) nut habit with or without tobacco use can (viii) Sideropenic dysphagia.
cause cytogenetic changes in oral epithelium. Various
other chewing habits, usually combinations that con- (ix) Palatal changes associated with reverse smoking
tain tobacco, are used in different cultures (e.g., Qat, (leukokeratosis nicotina palatinae).
Shammah, and Toombak). Tobacco chewing by peo- (x) Discoid lupus erythematosus.
ple from parts of Asia appears to predispose to OSCC, (xi) And others.
particularly when it is started early in life and is used
frequently and for prolonged periods [3, 5, 6]. Studies Prognostic Factors
from India have confirmed the association between
paan tobacco chewing and OSCC, particularly cancer (a) Patient’s factors:
of the buccal and labial mucosa [3].
(1) Age.
(iv) Diet: a significant protective effect of diet against (2) Sex.
oral cancer has generally been shown in persons (3) General condition of the patient and preopera-
who consume beta-carotene-rich vegetables and citric tive haemoglobin level.
fruits [3].
(4) Tolerance.
(v) Mouthwash use: the effect of the alcohol in mouth- (5) Occupation.
wash appears to be similar to that of alcohol used for (6) Acceptance and compliance.
drinking although the contribution of mouthwash use (7) Lifestyle.
to oral cancer must be small in terms of attributable
(8) Socioeconomic status.
risk. This controversy continues [7, 8].
(vi) Socioeconomic status: behaviors that lead to social (b) Tumour’s factors:
instability or social instability itself have been linked
(1) Size.
to an increased risk of oral cancer, but many other
explanations may exist (e.g., habits, oral health, diet, (2) Site.
and nutrition) [7]. (3) Locoregional metastasis.
(4) Histology of tumour.
(vii) Infective agents: Candida albicans and viruses, such as
(5) Degree of differentiation.
herpes viruses and papillomaviruses, may be impli-
cated in some cases. Human papillomaviruses are (6) Margin of the tumour after surgery.
particularly implicated in oropharyngeal cancers [3, (7) Thickness of the tumour (degree of invasion).
9]. (8) Volume of the tumour.
(9) Speed of the growth which may reflect its
(viii) Others: associations also are apparent between oral
biological behavior.
cancer and other various oral conditions (e.g., oral
submucous fibrosis, oral lichen planus, lupus erythe- (c) Team’s factors:
matosus, dyskeratosis congenita, and Fanconi ane-
mia) [3]. (1) It is affected by the patient’s factors and tumour’s
factors.
Smoking and alcoholism are dominant risk factors, being (2) The ability of the center and its facilities.
found in the past history of 75% of the patients with oral
(3) Skills of the surgeons and their experience.
cavity cancers. A frequency of 2–4 times greater of squamous
carcinoma in smokers has been observed, and the risk is (4) Skills of radiotherapists and chemotherapists
rising up to 6–15 times in association with chronic alcoholism and their experience.
[10, 11]. Epidemiological studies showed a high risk for this (5) Availability and skills of dental and prosthetic
disease for the families with a history of head and neck services.
cancers [12]. (6) Availability and skills of rehabilitation services.
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Journal of Oral Oncology 3

Table 1: T—primary tumour.

TNM FIGO
TX Primary tumour cannot be assessed
T0 No evidence of primary tumour
Tis Carcinoma in situ
T1 Tumour 2 cm or less in greatest dimension
T2 Tumour more than 2 cm but not more than 4 cm in greatest dimension
T3 Tumour more than 4 cm in greatest dimension
T4a (lip) Tumour invades through cortical bone, inferior alveolar nerve, floor of mouth, or skin (chin or nose)
T4a (oral cavity) Tumour invades through cortical bone, into deep/extrinsic muscle of tongue (genioglossus, hyoglossus,
palatoglossus, and styloglossus), maxillary sinus, or skin of face
T4b (lip and oral cavity) Tumour invades masticator space, pterygoid plates, or skull base or encases internal carotid artery
Note: superficial erosion alone of bone/tooth socket by gingival primary is not sufficient to classify a tumour as T4.

(7) Availability and skills of supportive services Table 2: N—regional lymph nodes.
(skills and training of nursing staff, speech ther-
apist, clinical psychologist, and oral hygienist). NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
The outcome is greatly influenced by the stage of the Metastasis in a single ipsilateral lymph node, 3 cm or less
disease, the TNM classification, the tumour’s size, and locore- N1
in greatest dimension
gional metastasis (TNM) (Tables 1, 2, 3, and 4) [13]. N2 Metastasis as specified in N2a, 2b, 2c below
Metastasis in a single ipsilateral lymph node, more than
N2a
2. Methods 3 cm but not more than 6 cm in greatest dimension
Metastasis in multiple ipsilateral lymph nodes, none
A web-based search for all types of articles published was N2b
more than 6 cm in greatest dimension
initiated using Medline/PubMed, with the key words such Metastasis in bilateral or contralateral lymph nodes,
as oral cancer, prognostic factors of oral cancer, diagnostic N2c
none more than 6 cm in greatest dimension
method of oral cancer, and imaging techniques for diagnosis Metastasis in a lymph node more than 6 cm in greatest
of oral cancer. The search was subsequently refined. The N3
dimension
sites of specialized scientific journals in the areas of oral Note: midline nodes are considered ipsilateral nodes.
and maxillofacial surgery, oral medicine, and oncology were
also used. I give an overview of published studies on the
Table 3: M—distant metastasis.
prognostic factors of OSCC and diagnostic aids, emphasizing
on noninvasive diagnostic aids and the functional diagnostic MX Distant metastasis cannot be assessed
imaging that can be used in diagnosis of OSCC. The search M0 No distant metastasis
was restricted to articles published in English, with no M1 Distant metastasis
publication date restriction (last update April, 2013).
Table 4: Stage grouping.
3. Review of the Literature
Stage 0 Tis N0 M0
3.1. Site. The most commonly reported oral cancer sites Stage I T1 N0 M0
include the floor of the mouth (FOM) and lateral borders Stage II T2 N0 M0
of the tongue. The tongue, as a whole, is the most common T1, T2 N1 M0
(40–50%) site for oral SCC in European and American Stage III
T3 N0, N1 M0
population. Asian population usually suffers from cancer of
T1, T2, T3 N2 M0
the buccal mucosa due to betel quid/tobacco chewing habits; Stage IVA
buccal mucosa SCC constitutes 40% of OSCC in Sri Lankan T4a N0, N1, N2 M0
population [14]. Any T N3 M0
Stage IVB
There is a wide belief that involvement of anterior site is T4b Any N M0
usually associated with better prognosis than the posterior Stage IVC Any T Any N M1
site. Five-year survival is significantly reduced for more
posteriorly located tumours (i.e., oropharyngeal compared
to oral) [15]. Reduction in survival is largely explained by drainage of posterior part of the tongue is bilateral while
tumour’s site influence on nodal metastasis [16]; this can anterior part of the tongue is unilateral, and in general the
be linked to the lymphatic drainage of these locations and anterior part of the oral cavity drains at the upper part of
ability of locoregional surgical management. The lymphatic cervical lymph node while the posterior part drains more
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4 Journal of Oral Oncology

inferiorly, and it is well known that involvement of the upper as an important predictor of regional recurrence, distant
part of lymph node is usually associated with better prognosis metastasis, and, thus, overall survival.
than the inferior part. Factors that seem to influence tumour spread to the
lymphatics include
3.2. Size. The overall 5-year survival has been reported to (i) tumour primary site (the posterior site is worse than
vary in range according to tumour size (T1/T2 commonly the anterior site of oral cavity);
referred to as “low-risk tumours” and T3/T4 commonly
(ii) tumour thickness (as tumour thickness increased the
referred to as “high-risk”). The outcome is greatly influenced
prognosis became poor);
by the stage of the disease (especially TNM) [17]. Prognosis
also depends or varies with tumour primary site, nodal (iii) double DNA aneuploidy (aneuploidy is an abnormal
involvement, tumour thickness, and the status of the surgical number of chromosomes);
margins. Moreover, the cumulative effects of tobacco, betel (iv) poor differentiation (poor differentiation means
nut, and alcohol decrease the survival rate [18]. Soo in 1988 aggressive biological behaviour).
reported on 283 of squamous cell carcinoma; he found 30%
diagnosed at T1, 48% at T2, 17% at T3, and 11% at T4. He (a) The pathological aggressiveness of disease
reported 95% of the cases required resection, 32% required (including rapidity of growth, locoregional, and
marginal resection, and 63% required segmental resection. distance spread) is strongly depending on the
The survival rate is closely related to stage of tumour at biological behaviour of the tumour which is not
time of diagnosis. Five-year survival rate is 77% at stage I, included in TNM classification.
70% at stage II, 42% at stage III, and 24% at stage IV. The (b) Brandwein in 2005 reported that a weak or
tumour size usually affects choice and outcome of treatment limited lymphocyte response at the tumour-host
[15]. It also affects the surgeon’s ability to achieve complete interface is strongly associated with local recur-
resection, especially in deep invading tumours. Increased rence and death. Hiratsuka in 1997 reported an
tumour size has been linked to cervical involvement [16, 19], adverse relationship between lymphocytic infil-
high recurrence rate [16, 20], and poor prognosis [21, 22]. trate and nodal disease and overall prognosis.

3.3. Tumour Volume. Tumour volume (tumour thickness) is Distant metastasis was reported in 5–25% of OSCC
closely related to lymph node metastasis, and it is believed patients [29] most commonly in poor locoregional control.
that it reflects the aggressiveness of tumour growth [23]. It is Distance metastasis is usually reported in N2/N3. Extracap-
believed that the amount and nature of lymph node metas- sular spread is a very important determent as it significantly
tasis are closely related to size and thickness of tumour. The increases the risk of distance metastasis.
relationship between thickness of the primary tumour and There is a wide belief that ultrasound guided fine needle
occurrence of contralateral cervical metastasis was reported aspiration biopsy is best way for evaluation of lymph node
to increase by 5% in T1/T2 SCC of the oral tongue [24], involvement. In some studies a 100% sensitivity in oral SCC
and it is believed that contralateral lymph node involvements has been reported for this method.
have a poorer prognosis than ipsilateral involvement. It has Cervical metastasis by a tumour is a firm statement of its
been found that the size of lymph node involvement is aggressive malignant nature. Nothing is more controversial
closely related to tumour volume (thickness). It is now widely than the management of cervical metastatic disease. It is
accepted that thickness is more accurate predictor of sub- well recognized that the presence of cervical metastasis is
clinical nodal metastasis, local recurrence, and survival than the most important prognostic factor in head and neck
tumour size [16]. Tumour diameter is not the most accurate squamous cell carcinoma, accounting for a 50% reduction
when compared to tumour thickness or depth of invasion, in the five-year survival rate for ipsilateral cervical lymph
which can be related directly to prognosis. Tongue OSCC of node metastasis [30–32] and 75% reduction in case of bilateral
5 mm thickness increases the cervical metastasis significantly metastasis [33, 34]. When the risk of metastasis exceeds 15–
[25]. Tumour at the floor of the mouth with thickness of 2 mm 20%, neck dissection or radiation therapy is indicated [35, 36].
should lead to the consideration of elective nodal surgical Most tumours have a predictable pattern of neck metastasis.
treatment of the neck [26]. A poor prognosis should be The main routes of the cervical lymph node metastasis are
considered if the tumour thickness of buccal mucosa OSCC through the first station nodes [37, 38] Levels I and II,
is 6 mm or more [19]. followed by the second station nodes which include Levels
III, IV, and V. The metastatic node was seen in Level I
(70%) followed by Level II (66.7%) and Level III (33.3%)
3.4. Lymph Node Involvement. Bad prognosis is expected [37, 38]. The incidence of false-negative (occult) nodes based
in patients with ipsilateral, contralateral or bilateral nodal on palpation varies in the literature from 27 to 38%. The
involvement. The worst is bilateral then contralateral, then sensitivity and specificity of palpation are in the range of 60–
ipsilateral. The size of nodal involvement is a very important 70% [34, 35, 39]. Ultrasound guided fine needle aspiration
determent. The incidence of occult lymph node metastasis in biopsy is a very promising technique in detection of lymph
early stage tumours (T1/T2) has been reported to be between node metastasis. The reported sensitivity of sonography for
27% and 40% [27, 28]. Extracapsular invasion was identified detecting lymph node metastases ranges from 63% to 97%
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Journal of Oral Oncology 5

and specificity ranges from 74% to 100% [40]. The use of is one of the most efficient ways to reduce the high mortality
FDG-PET scanning in diagnosis of lymph node involvement from this disease. Early detection can minimize the morbidity
is controversial and many institutions use MRI or ultrasound of the disease and its treatment, which is associated with a
guided biopsies rather than PET scans. severe loss of function, disfigurement, depression, and poor
quality of life.
3.5. Degree of Differentiation. According to the degree of ker-
Noninvasive Diagnostic Aids
atinisation, cellular and nuclear pleomorphism, and mitotic
activity, the squamous cell carcinoma is categorised into three (i) Toluidine blue.
categories:
(ii) Oral brush biopsy.
(i) well differentiated, (iii) Saliva-based oral cancer diagnosis.
(ii) moderately differentiated, (iv) Light-based detection systems: optical biopsy.
(iii) poorly differentiated.
(a) Chemiluminescence (ViziLite Plus; Microlux/
The influence of histologic grading as a prognostic factor DL, Orascoptic-DK).
in OSCC was assessed in 215 patients by Kademani in 2006, (b) Tissue fluorescence imaging (VELscope).
and he found that the degree of differentiation is a significant
predictor of locoregional failure and tumour recurrence. (c) Tissue fluorescence spectroscopy.

(v) Biomarkers:
3.6. Invasive Front. Invasive front is a term used for describ-
ing the nature of invasion of the tumour at the host-tumour (a) DNA-analysis.
interface as this relation reflects the biological behavior of
the tumour. The pattern of invasion can be assessed by using (vi) Laser capture microdissection.
(Anneroth and Bryne) criteria: Grade 1 tumours had well-
delineated “pushingor cohesive” borders. In Grade 2, the Invasive Diagnostic Aid
advancing edge of tumour infiltrated in solid cords, bands,
or strands. Grade 3 tumours had margins that contained (i) Surgical Biopsy.
small groups or cords of infiltrating cells. In Grade 4, there
is marked dissociation in small groups or even single cells 3.8. Toluidine Blue (TB) Staining. Toluidine blue (TB) stain-
(noncohesive). Endophytic growth pattern is associated with ing is a simple, inexpensive, and sensitive tool for identifying
increased local recurrence. High grades of infiltration (Grade early OSCC and high-grade dysplasias [41]. A 1% aqueous TB
3 or 4) are usually associated with nodal involvement and solution is applied for 30 seconds; this acidophilic metachro-
subsequent disease metastasis. matic nuclear stain helps to differentiate areas of carcinoma
in situ or invasive carcinoma from normal tissue. Toluidine
3.7. Perineural and Endoneural Invasion. Perineural and blue is highly sensitive and moderately specific for malignant
endoneural invasion is strongly associated with lesions. The sensitivity is decreased for premalignant lesions
with up to 58% false negative reported for identifying mild-
(i) tumour size, to-moderate dysplasia [42, 43]. Rosenberg and Cretin stated
(ii) histological grading, that the sensitivity of toluidine blue staining in oral cancer
screening has been found to range from 93.5% to 97.8%, and
(iii) invasive front, to specificity ranged from 73.3% to 92.9% [44].
(iv) nodal involvement.
3.9. Oral Brush Biopsy. The accuracy of the brush test has
The perineural spread is affecting overall prognosis and
been the subject of many published studies. In every study
survival [15], because the perineural and endoneural invasion
in which an oral lesion was simultaneously tested with both
means spreading of the tumour cells up to base of the skull
a brush biopsy and surgical biopsy, this test has been shown
as the tumour cells spread easily though the nerve and
to have a sensitivity and specificity well over 90% [45, 46].
surrounding tissues and compartment.
the brush biopsy collects cells from the full thickness of the
Prognostic value of perineural invasion has been oral epithelium. The brush biopsy has so many advantages:
highlighted in several studies and linked to regional it is a chair side, easy to perform, and painless test that can
recurrence and distant metastasis. be used to evaluate any suspicious lesion including common
small white and red oral lesions to rule out dysplasia. To
The five-year survival was 53% during the time period help localize the optimal site for brushing an abnormality,
from 1975 to 77 and has increased to 63% between 1999 and Gupta in 2004 combined conventional oral brush biopsy with
2005 this difference was found to be statistically significant; the application of toluidine blue to localize suspect mucosal
using newer diagnostic modalities that detect the disease in areas [42]. Scully stated that the sensitivity of brush biopsy in
its early stage and/or using newer chemotherapeutic options detection of dysplasia or OSCC was 71.4% but the specificity
may explain this improvement. Early detection of oral cancer was only 32% [47].
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6 Journal of Oral Oncology

3.10. Saliva-Based Oral Cancer Diagnosis. Saliva-based oral in fluorescence spectroscopy technologies was up to 81% and
cancer diagnosis is a noninvasive alternative to serum testing; specificity was 100% [53].
it is an effective modality for diagnosis, determining progno-
sis of oral cancer and for monitoring posttherapy status. A 3.12.2. Enhanced Dye Fluorescence. Photodynamic drug can
significant increase in salivary concentrations of Cyfra 21-1, be applied which enhanced porphyrins such as protopor-
Tissue Polypeptide-specific Antigen (TPS), and cancer anti- phyrin IX (protoporphyrin IX is an important precursor
gen 125 (CA125) was shown with sensitivity of 71%, specificity to biologically essential prosthetic groups such as heme,
of 75%, and negative value of 71% and positive predictive cytochrome c, and chlorophylls). The fluorescence is slightly
values of 75%. On the other hand Carcinoembryonic antigen enhanced by using exogenously applied fluorescent drugs
(CEA), and cancer antigen 19-9 (CA19-9), did not reach (e.g., 5-aminolevulinic acid induced protoporphyrin IX).
statistical significance [48, 49]. Recent advances include the possibility to extract true spectra
of single fluorophores (chemical compound that can reemit
3.11. Light-Based Systems. Light-based systems that are based light upon light excitation) by mathematically eliminating
upon the assumption that abnormal metabolic or structural the undesired influences of scattering and absorption. As
changes have different absorbance and reflectance properties well, tumour-specific enzymes are about to be specifically
for lights. ViziLite Plus with TBlue system (Zila Pharmaceuti- targeted by fluorescent markers “smart probes” in order to
cals, Phoenix, Arizona, U.S.), VELscope (LED Dental, White improve both sensitivity and specificity [54–56]. Ebenezar
Rock, British Columbia, Canada), Microlux/DL (AdDent stated that the diagnostic algorithm based on discrimi-
Inc, Danbury, Connecticut), and Orascoptic DK (Orascoptic, nant function scores obtained by fluorescence excitation
Middleton, WI) are light-based oral cancer screening aids spectroscopy (FES) method was able to distinguish well-
that have been developed and aimed at assisting in the identi- differentiated squamous cell carcinoma from normal lesions
fication of precancerous and cancerous lesions at their earliest with a sensitivity of 100% and specificity of 100% [57].
stage. VELscope is a handheld device with an illuminated
chemiluminescent light stick that uses visible light in the 3.12.3. Ratio Imaging. This technique compares a photo-
430 nm wavelength in order to cause fluorescent excitation chemical or end metabolic product which is known to be
of certain compounds in the tissues. The patients first rinse increased in disease status to another product which is
with acetic acid, and then the oral cavity is examined. In known to be depleted. The 5-aminolevulinic acid enhances
Microlux and Vizilite, the oral cavity is examined with a protoporphyrin IX which fluoresces red after excitation with
battery-powered fiber-optic visible light source instead of blue light. The same excitation results in green fluorescence
a chemiluminescent and that requires that the patient first of molecules such as NAD and FADH, which are depleted in
rinses with acetic acid. These devices are not sensitive or high metabolic rate of malignant tissues [54–56]. Shin stated
specific for diagnosis of any type of abnormal oral lesion. that the sensitivity of the fluorescence imaging techniques
Only a definitive test, examining tissues, can determine the ranged from 60 to 97% and specificity from 75 to 99% [58].
biologic behavior of a lesion [50].
3.12.4. Raman Spectroscopy. Is laser-based technique that
enables chemical characterization and structure of molecules
3.12. Tissue Fluorescence Spectroscopy
in the sample. It helps to obtain a vibrational spectroscopic
3.12.1. Autofluorescence Spectroscopy. In case of malignancy picture of the tissue content, thus provide immediate real
there are changes in the physical and chemical characteristics time histology [54–56]. The technique is used to observe
of the tissues due to the subcellular architectural changes vibrational, rotational, and other low-frequency modes in a
in cancer, such as nuclear grade and nuclear to cytoplasm system. The Raman effect occurs when light impinges upon a
ratio, mitochondrial size and density, amount of keratin, molecule and interacts with the electron cloud and the bonds
and elastin to collagen ratio, and it is well known that all of that molecule. For the spontaneous Raman effect, which is
tissues fluoresce and malignant tissues fluoresce less than a form of light scattering, a photon excites the molecule from
normal tissues, they have different spectral characteristics. the ground state to a virtual energy state. When the molecule
Studies of these methods in normal oral mucosa have shown relaxes it emits a photon and it returns to a different rotational
increased green fluorescence in comparison to neoplastic or vibrational state. The difference in energy between the
lesions upon ultraviolet (UV) or near UV light source. Auto- original state and this new state leads to a shift in the emitted
fluorescence imaging has recently been shown to improve photon’s frequency away from the excitation wavelength [54–
the detection of premalignant and malignant oral lesions. 56]. The reported sensitivity of this technique was of 80.5%
This method is based on the illumination in the absorption and specificity of 86.2% [59].
of tissue fluorophore molecules (NADH and FAD in the
epithelial layer and collagen and elastin in the stroma) in 3.12.5. Elastic Scattering Spectroscopy. The system uses a
ultraviolet visible spectrum leading to the emission of lower wide band of wavelengths from 400 nm up to 700 nm and
energy photon that can be detected as fluorescence from the recovers the scatter power, scatter amplitude, and absorption
oral surface mucosa. Optical fibres may be introduced into species from the reflectance from a 100 micron spot, allowing
the tissues through a hollow needle; the tissue signals are imaging of tissue at high frame rate. Thus the ESS is the
interpreted by spectrometers [51, 52]. The reported sensitivity optical signature of the tumour which greatly depends on the
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Journal of Oral Oncology 7

morphology of the tumour. The probe of the system should A computer-assisted analysis has been recently designed to
be in contact with the tissues, and no light is collected from identify deviations of cellular DNA content [48, 64].
the surface reflections. Absorption characteristic provides the
optical signature of the tissue [54–56]. Lovat et al stated 3.14. Laser Capture Microdissection. It is a precise study of
that the sensitivity was 92% and specificity was 60% and cancer biology which helps in defining the molecular basis
it differentiated high risk sites from inflammation with a of malignancy [50]. LCM technology based on extraction of
sensitivity and specificity of 79% [60]. cells from specimens in which the exact morphology of both
the captured cells and the surrounding tissue is preserved.
3.12.6. Differential Path-Length Spectroscopy (DPS). Differen- When rapid immunohistochemical staining techniques are
tial path-length spectroscopy is a recently developed fibre- combined with LCM, more accurate microdissection of
optic point measurement technique that measures scattered cellular subsets can be obtained [65]. It may also help to
photons that have travelled, and their predetermined path detect the biomarkers and protein fingerprint models for
lengths are measured. The spectrum is analyzed mathemati- early detection of oral SCC.
cally and is translated into a set of parameters that are related
to the microvasculature and to the intracellular morphology. 3.15. Lab-on-a-Chip. It is the adaptation, miniaturization,
The reported sensitivity was 69% and specificity was 85% [61]. integration, and automation of analytical laboratory pro-
cedures into a single device or electronic chip. It uti-
3.12.7. Spectral Scatter Scanning System. The system uses lizes membrane-associated cell proteins to detect dysplastic
dark field illumination and spectrometer detection in the changes that are singularly expressed on the cell membranes
emission channel together with a scanning mirror. This of dysplastic and cancer cells as well as their unique gene
system has been evaluated for imaging the spectral signature transcription profiles [66].
remitted from tissue, with real-time classification algorithm;
the system uses a wide band of wavelengths from 400 nm
3.16. Imaging Techniques in Diagnosis of Oral SCC. Chest
and up and recovers the scatter power, scatter amplitude, and
radiography may be indicated because the lungs are the most
absorption species from the reflectance from a 100-micron
common site for metastases. It demonstrates metastasis to the
spot; this allows imaging of tissue at high frame rate [62].
lungs or hilar lymph nodes, ribs, or vertebrae. Radiography
may be including axial CT scanning or, possibly, other
3.12.8. Nuclear Magnetic Resonance Spectroscopy. This tech- imaging techniques may be needed to determine the degree
nology allows three-dimensional study of atoms in the of spread of some tumours, particularly to exclude bone
molecule; the larger the magnet, the more sensitive the invasion and lymph node involvement.
device. It is possible to view the way of protein link up to DNA Other imaging investigations include MRI or CT scan-
[54–56]. ning of the primary sites of the head and neck and of
suspected sites of lymph node or distant metastases.
3.12.9. Optical Coherence Tomography. It is analogous to Bone scanning is of little value in screening because
ultrasound imaging except that it uses light rather than findings are positive only where bone involvement is symp-
sound. The high spatial resolution of OCT enables nonin- tomatic, so radionuclide scanning is occasionally useful. Liver
vasive in vivo “optical biopsy” and provides immediate and radionuclide scanning shows abnormal findings in as many
localized diagnostic information. The recent development of as 6% of patients with cancer in the head and neck, but two
a Fourier-domain-mode-lock (FDML) swept source based thirds are false-positive findings; therefore, liver scanning
OCT system helps in achieving a high speed (>100 kHz A- normally is not indicated [15].
scan rate) and high spatial resolution (<4 𝜇m) simultane- Scully stated that the routine panendoscopy helps in
ously. In addition, the development of various miniature identifying simultaneous second primary carcinomas in the
scanning probes that allow high-speed 3-dimensional OCT esophagus, larynx, or lungs in as many as 14% of patients.
picture can be reported [54–56]. Endoscopy is widely recommended although it is not per-
formed in all centers. More than one-third of SPTs are
3.12.10. Infrared Spectroscopy. It distinguishes different detectable by endoscopy at or within 1 year of diagnosis of
biomolecules by probing chemical bond vibrations and using the index tumours [15].
these molecular and submolecular patterns to define and Primary cancers of head and neck, such as HNSCC and
differentiate pathological from normal tissues [63]. non-Hodgkin’s lymphoma, are usually staged by MRI or CT.
Although MRI is still superior to CT for demonstrating the
primary cancer and relationship of cancer boundaries to
3.12.11. Confocal Endomicroscopy. It is a noninvasive optical normal anatomical structures, it is widely believed that CT
biopsy that helps in diagnosis of the pathology of gastroin- has advantage in demonstrating bone erosion over the MRI.
testinal, dermatologic, and ocular diseases. King stated that artifacts from swallowing, breathing, and
coughing limit the quality of MRI and become an increasing
3.13. Biomarkers: DNA-Analysis. It is a DNA ploidy analysis problem on moving down the neck. Therefore on descending
after staining with Feulgen dye to determine the malignant the head and neck the advantages of MRI decrease and those
potential of cells by comparing with a reference group of cells. of CT increase, so in general the MRI is preferred in the
 8283, 2013, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1155/2013/519312 by Readcube-Labtiva, Wiley Online Library on [18/09/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
8 Journal of Oral Oncology

skull base/nasopharynx and CT in the larynx. The MRI and tumours, as small as 3 mm, have been detected by PET
CT are usually the modalities of choice for imaging cancers imaging [80].
of the aerodigestive tract, US is the method of choice for PET scans are increasingly read alongside CT or magnetic
detecting cancers arising in glandular organs such as the resonance imaging (MRI) scans; the combination (“coregis-
thyroid and salivary glands by guided biopsy performed in tration”) gives both anatomic and metabolic information (i.e.,
the same examination. King stated that FDG-PET has a role what the structure is and what it is doing biochemically).
in the identification of the unknown primary tumour, but at Because PET imaging is most useful in combination with
present it has no proven additional value in staging patients anatomical imaging, such as CT, modern PET scanners are
with a known primary tumour [67]. now available with integrated high-end multi-detector-row
CT scanners. Because the two scans can be performed in
immediate sequence during the same session, with the patient
3.17. Functional Imaging Techniques. These techniques are
not changing position between the two types of scans, the
being used to assess the complex interrelated processes in
two sets of images are more precisely registered, so that areas
the cancer microenvironment, such as hypoxia, angiogenesis,
of abnormality on the PET imaging can be more perfectly
pH, and metabolism. These techniques have the potential to
correlated with anatomy on the CT images.
(1) improve prediction of the cancer behaviour and response
to treatment; (2) evaluate new drugs such as the antivascular
agents; (3) monitor early cancer response during treatment; 3.19. Diffusion-Weighted Imaging (DWI). DWI is an easy,
and (4) identify residual/recurrent cancer [67]. quick, and widely available functional MR technique. It
evaluates the mobility of water in different tissues to generate
diffusion weighted images and apparent diffusion coefficient
3.18. Positron Emission Tomography (PET). It is a nuclear
(ADC) maps. Diffusion weighted images are being used to
medicine imaging technique which produces a three-
identify a range of cancers, and the ADC value improves
dimensional image or map of functional processes in the
characterization of head and neck tumours, and the ADC
body. The system detects pairs of gamma rays emitted
of the mass lesions studied had an inverse relationship with
indirectly by a positron-emitting radionuclide (tracer), which
lesion cellularity [81–83]. The ADC values can also be used
is introduced into the body on a biologically active molecule.
to monitor cancer treatment. During treatment the ADC
Images of tracer concentration in 3-dimensional space within
value of cancer increases as a result of an increase in cell
the body are then reconstructed by computer analysis.
permeability and swelling, cell destruction, leakage of water
Positron emission tomography (PET) is a functional image
into extracellular space (EES), and necrosis. These changes
modality that characterizes the different tissues of the body
may occur early in treatment, preceding volume changes [67].
according to perfusion and metabolic activity of the glucose
analogue fludeoxyglucose F 18 (18 FDG). The 18 F-fluoro-2-
deoxy-D-glucose (FDG) is a radioactively labeled glucose 3.20. Dynamic Contrast-Enhanced Magnetic Resonance Imag-
analogue that is utilized due to its capacity to emit positrons, ing (DCE-MRI). DCE-MRI is performed after the admin-
and it can be accurately localized by PET imaging. As tumour istration of intravenous contrast medium to noninvasively
cells have an increased uptake of glucose, FDG accumulates access tumour vascular characteristics. DCE-MRI techniques
within these cells, producing a “hot spot” on the PET image so utilizing low-molecular-weight contrast media have success-
by this way, it can be distinguished from surrounding normal fully made the transition from methodological development
tissue [68, 69]. In the head and neck regions, PET showed to preclinical and clinical validation and are now rapidly
effectiveness in the detection of unknown primary tumours becoming mainstream clinical tools. The low-molecular-
[70–72]. Positron emission tomography is able to image weight agents (1000 Da) rapidly diffuse in the extracellular
and identify the location of previously unknown tumours fluid (ECF) space [84]. A malignant tumour of a few mm3
better than any other method, as has been shown in many in volume cannot rely on the passive diffusion of metabolites
studies [70, 73, 74]. The most important source of false- from host tissue blood vessels to be able to continue to
positive results in PET is the inflammatory tissue reaction. proliferate, so new vasculature must develop in order for the
Positron emission tomography proved to be the most reliable tumour to continue to grow [85, 86]. This process of new vas-
procedure for detecting recurrent carcinoma. cularization or angiogenesis [86] is a signature of neoplasms
The utility of PET imaging has been demonstrated in the and one of the principal potential targets for quantitative
diagnosis and initial staging of head and neck tumours as imaging [87]. It is widely believed that all solid tumours are
well as in the evaluation of persistent or recurrent disease dependent upon angiogenesis for survival [88], and many
following radiotherapy [75, 76]. Others have shown the antiangiogenic drugs are currently in clinical trials [89]. Thus,
benefit of PET in the detection of unknown primary head methods for imaging and quantitatively assessing this phe-
and neck cancers or synchronous primary tumours [77, 78]. nomenon will be useful in clinical oncology [90]. The tumour
One advantage of PET over other imaging modalities, such vessels produced by angiogenesis are characteristically leaky,
as computed tomography (CT) or magnetic resonance imag- fragile, and incompletely formed unlike mature blood vessels
ing (MRI), is that since PET imaging visualizes metabolic that are the result of normal physiologic processes [85, 86].
processes in vivo, relatively small tumours can be detected Dynamic contrast-enhanced magnetic resonance imaging
before structural changes have taken place, as long as they (DCE-MRI) is an imaging technique that can measure the
are metabolically active [79]. In fact, previously unapparent density, integrity, and leakiness of tissue vasculature. Changes
 8283, 2013, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1155/2013/519312 by Readcube-Labtiva, Wiley Online Library on [18/09/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Journal of Oral Oncology 9

in the parameters obtained by DCE-MRI can be used to assess respond to this kind of treatment. It uses a T-sensitive
longitudinal changes within a tumour and, in particular, how sequence during oxygen inhalation to detect an increase in
a tumour is responding to treatment. The method is based on signal resulting from the reduced paramagnetic effect of a
measurements and mathematical models of how a tracer per- reduction in the blood deoxyhaemoglobin within a cancer.
fuses through such vessels. Healthy vessels in normal tissues As with all functional MR techniques, BOLD presents chal-
may be characterized by a range of parameters: measuring lenges: the signal is not purely the result of oxygenation, the
blood flow, vessel permeability, and tissue volume fractions effects are short lived, and signal changes are small and may
(i.e., fractions of a given sample of tissue that can be attributed be difficult to reproduce. However, despite these difficulties,
to intravascular or extravascular space). It is hypothesized BOLD has been used successfully to detect decreased hypoxia
that some or all of these parameters will be different in in the blood (deoxyhaemoglobin in human cancers) during
pathologic vessels. In recent years, there have been great carbogen inhalation [67, 94, 95] and shows promise for
interest and considerable development in the use of DCE- tailoring treatment for hypoxic cancers in the future [67].
MRI to study these phenomena and test this hypothesis [90].

3.21. Magnetic Resonance (MR) Spectroscopy. It is a noninva- 4. Conclusion

sive diagnostic test for measuring biochemical changes in the
There is wide belief that the OSCC at the anterior site of oral
tumours. While magnetic resonance imaging (MRI) identi-
cavity is usually associated with better prognosis than the
fies the anatomical location of a tumour, MR spectroscopy
posterior site; the reason behind this is the sites of lymphatic
compares the chemical composition of normal tissue with
drainage. The lymphatic involvement considered as the most
abnormal tumour tissue. MR spectroscopy is conducted
important determent in prognosis of OSCC. The tumour size
on the same machine as conventional MRI (see magnetic
is an important factor in lymphatic involvement and it usually
resonance imaging). The MRI scan uses a powerful magnet,
affects the choice and outcome of treatment. Tumour thick-
radio waves, and a computer to create detailed images.
ness is more critical than the size of the tumour in terms of
Spectroscopy is a series of tests that are added to the MRI scan
prognosis, and it is closely related to lymph node metastasis.
to measure the chemical metabolism of a suspected tumour.
It is believed that it reflects the aggressiveness of tumour
MR spectroscopy analyzes molecules such as hydrogen ions
growth. The tumour primary site, tumour thickness, and
or protons. Proton spectroscopy is more commonly used
degree of differentiation are the most important determents
[91, 92]. There are several different metabolites, or products
for lymphatic involvement. The perineural spread is affecting
of metabolism, that can be measured to differentiate between
overall prognosis and survival because the perineural and
tumour types. MRS provides biochemical information of
endoneural metastases mean spreading of the tumour cells
compounds present in human tissue and cells. Human brain
up to the base of the skull as the tumour cells spread easily
contains hundreds of metabolites, but the proton MRS can
though the nerve and the surrounding tissues and com-
only detect a few of them as the least millimolar concen-
partment. The rapidity of growth, locoregional spread, and
trations are necessary for the metabolites to be detected.
distance spread are the factors that reflect the pathological
The major brain metabolites detected are choline (Cho),
aggressiveness of disease. Distant metastasis was reported
creatine (Cr), N-acetyl aspartate (NAA), lactate, myoinositol,
in 5–25% of OSCC patients [29], most commonly in poor
glutamine and glutamate, lipids, and the amino acids leucine
locoregional control. Early detection of oral cancer is one of
and alanine [91]. The frequency of these metabolites is
the most efficient ways to reduce the high mortality from this
measured in units called parts per million (ppm) and plotted
disease. Early detection can minimize the morbidity of the
on a graph as peaks of varying heights. By measuring each
disease and its treatment, which is associated with a severe
metabolite’s ppm and comparing it to normal tissue, the type
loss of function, disfigurement, depression, and poor quality
of tissue present can be determined [92]. MRS demonstrates
of life. There is an urgent need to devise critical diagnostic
chemicals or metabolites within cancers that can be used as
tools for early detection of oral dysplasia and malignancy
biomarkers to identify cancer and explore changes associated
that are practical, noninvasive and can be easily performed
with hypoxia and cancer treatment. Proton (H) and phospho-
in an outpatient set-up. Toluidine blue is highly sensitive
rus (P) changes in Cho are currently under interrogation for
and moderately specific for malignant lesions and can be
monitoring cancer treatment and have been shown already
used for detection of the suspected areas. The brush biopsy
to be of value in the breast. Lactate is another biomarker that
is a reliable technique which equal to surgical biopsy as it
has been found in metastatic nodes from HNSCC and has the
collects cells from the full thickness of the oral epithelium.
potential to be used in the assessment of cancer hypoxia [93].
Tissue polypeptide-specific antigen (TPS) and cancer antigen
125 (CA125) are the most critically elevated tumour markers
3.22. Blood Oxygen Level-Dependent MRI (BOLD). It is well in saliva-based oral cancer test; other tumour markers are
known that hypoxic cancers are more resistant to radio- insignificantly elevated. Optical diagnostic technologies are
therapy and chemotherapy. Currently there is an interest techniques that help in early detection of oral dysplasia
in improving the therapeutic response of hypoxic cancers and malignancy. They are practical, noninvasive and can be
to radiotherapy by using radiosensitisers such as carbogen. easily performed in an outpatient set-up. The chemilumi-
BOLD is a noninvasive test using MRI that can identify nescence (ViziLite Plus; Microlux/DL, Orascoptic-DK) and
hypoxic cancers (deoxyhaemoglobin) which are likely to Tissue fluorescence imaging (VELscope) are technologies
 8283, 2013, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1155/2013/519312 by Readcube-Labtiva, Wiley Online Library on [18/09/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
10 Journal of Oral Oncology

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