Oral cancers have a high potential of spreading to cervical
lymph nodes. Therefore one of the most important factors
affecting long-term survival is the clinically manifest cervical
lymph-node status at the time of diagnosis[1,2].
When nodal metastases are present, nobody can deny the important
effect of therapeutic neck dissection in the prognosis
of head and neck cancer patients. However, Management of
the cN0 in oral cancer has been a matter of discussion. Even
in the absence of clinical proven metastases (cN0), there is
generally a high rate of occult metastases, which strongly depends
on the localization as well as the extent of the primary
tumor. Management of the cN0 neck is therefore considered
crucial. Several publications of surgically treated patients
have provided pathological data allowing estimating the risk for subclinical nodal involvement (i.e. occult metastases),
which ranges from 5% to 62.2%.[3-5] Such estimates
of risk are an important basis for rationally based decisions
as to which loco-regional treatment concepts should be used
. The N0 neck can be treated electively or can be carefully
observed (wait-and-see), and the decision is based on risk
calculations and clinical experience. Historically, treatment
ranged from elective radical neck or elective radiation of the
neck to watchful waiting policy.
Material and Methods
A computer literature search in MEDLINE, EMBASE, the
Cochrane library and the Cochrane Central Register of Controlled
Trials (CENTRAL) databases was performed by two
of the reviewers (A.H. and M.E.) in order to identify the studies
that answered the questions of interest. For this purpose
the following free-text terms were used: Oral Squamous Cell
Carcinoma, Clinically Negative Neck, Sentinel Lymph Node Biopsy, Wait and See Policy or observation, ultrasound-guided
fine-needle aspiration cytology. There were no restrictions
regarding time and language. Additionally, extensive hand
searching of the references of all the relevant studies was also
Selection of the studies
All the criteria for inclusion/ exclusion of the studies in the
present systematic review were specified prior to the literature
search. In order for the current study to be eligible, the following
criteria were established. The inclusion criteria include
the following: the study should include patients treated for
clinically negative neck of OSCC. The study should report the
management of the initial OSCC. The study should include a
comparison of the diagnostic methods for the neck metastasis
in OSCC. The study should include comparison of different
methods for treatment of the clinically negative neck of OSCC.
The studies that not offer the inclusion criteria were excluded
from the systematic review.
The electronic search resulted in the identification of 976 publications.
Subsequently, the titles of these manuscripts were
examined to exclude the irrelevant studies, which resulting
in 281 potentially eligible publications. The abstracts of these
studies were evaluated and only 61 studies were included in
the current systematic review, which could provide data to answer
the research questions. Eventually, only 27 studies were
matched the inclusion criteria and they were assessed independently
by two of the reviewers (A.H. and M.E.). (Table 1)
[7-33]. The studies excluded because they did not properly address
the research questions, or they did not include appropriate
statistical analysis, they were letters to editor, case report
Data extraction was performed by two of the reviewers (A.H.
and M.E.). The following data was recorded from the included
studies: type of the study, number of patients included in the
study, type of diagnostic procedures, type of management of
the neck (neck dissection, radiotherapy, wait and see policy or
combination therapy) and recurrence or failure.
Two reviewers independently assessed the methodological
quality of each article in term of internal and external validity,
based on the recommendation of the Cochrane handbook of
for systematic reviews of interventional .
27 studies fulfilled the inclusion criteria. The studies published
between 1999 and 2013. 15 studies were prospective studies
while the other 12 studies were retrospective studies. A total
of 3867 patients were reviewed (neck dissection= 2291 with
recurrence in 148 patients, wait and see = 1523 with recurrence
in 406 patients, radiotherapy = 11 with recurrence in 6
patients, combined therapy 42 with recurrence in 9 patients).
Sentinel lymph node biopsy was used in 734 with failure in 19
patients while ultrasonography-guided cytology (USgFNAC)
was used in 1107 with failure or recurrence in 236 patients
It is well known that 6% to 46% of patients with head and
neck cancer who have no palpable disease in their necks will
harbor occult disease in their necks . Beside, Cervical
nodal staging is a major challenge. Basic studies by Lindberg
 and Shah  demonstrated that SCCOC lymphatically
tends to spread in a predictable way. According to Shah, who
performed 192 radical neck dissections in patients suffering
from oral cancer having a cN0 neck (with no clinically palpable
metastases), these tumors mainly spread to level I-III .
These findings indicate that selective removal of the nodes in
these specific levels should remove the vast majority of possibly
tumor-positive nodes. However, a number of authors [38-40] emphasize that ‘skip metastases’ occur in a considerable
amount of treated cN0 oral cancer patients: in these patients
level I and II were not affected, while III and/or IV were. No
consensus has been reached yet and the extent of neck dissection
varies per medical center.
Clinical examination is influenced by the skill of the examiner,
the patient's body habits and whether the patient has had
previous surgical or irradiation therapy. As a result of these
factors, clinical examination associated with high rate of false
negative, and should be supplemented with diagnostic tools
like CT scan and ultrasonography .
Also, there is no method of pretreatment imaging or other
examination that will detect microscopic foci of metastatic
disease in cervical lymph nodes. Immunohistochemical and
molecular analysis of neck specimens reveals the incidence
of occult metastases to be higher than revealed by light microscopy
with ordinary hematoxylin and eosin staining. Occult
regional metastasis may be found even in cases with small
Controversies in the treatment of negative neck in oral cancer
arise due to different question that facing the surgeons treating
such cases, these issues include the following: What is the optimal
pre-treatment modality for diagnosing the cervical lymph
nodes metastasis? Should a patient with a cN0 neck treated
now or wait and see? Should the patient receive an elective
neck dissection or should they be treated with elective neck
radiation'? Are there prognostic factors that can guide us in
our decisions in treating the neck? Which modality should be
used for treating the neck? What are the future trends?
The answer is continuously debated, but surgeons believe
management decisions should rely on the incidence of occult
metastatic disease for a given tumor and its sub site. Finally,
the decisions to treat a clinically negative neck should
be based on the risk- benefits of the morbidity associated with
treatment and the incidence of occult metastases for a given
What is the pre-treatment modality for diagnosing
the cervical lymph nodes metastasis?
Ideally, the decision about treatment of an N0 neck would be
simplified if there were a highly accurate, noninvasive diagnostic
modality that could identify metastatic lymph nodes.
Studies have shown that the sensitivity, specificity, and accuracy
of detection of neck metastases by clinical examination
are 70%, 65%, and 68%, respectively. The assessment of the
status of the neck nodes is often based on palpation, although
this is generally accepted to be inaccurate. The overall error in
the assessment of the presence or absence of cervical lymph
node metastasis is 20 to 30%. Histopathological evaluations
have demonstrated that both the false-positive and the falsenegative
rate are unsatisfactorily high, causing over- and under
treatment in many patients .
Modern imaging techniques, such as computed tomography
(CT), magnetic resonance imaging (MRI), ultrasound (US)
and especially US-guided fine-needle aspiration cytology, are
more reliable than palpation .
CT and MRI are widely used to stage the neck but are limited
by the facts that the size of the lymph nodes must be at least 5
mm before they can be detected by either of these modalities,
cellular metastatic disease may not produce gross changes in
the node, and even grossly abnormal nodes may remain undetected
in some examination. MRI, by virtue of its high contrast
resolution and multiplanar capacity, has advantages over CT
for staging primary tumors of the head and neck region, while
CT is faster, cheaper, and marginally more accurate than MRI
in staging cervical nodes .
Dynamic contrast-enhanced MRI has been applied for differentiating
normal from metastatic lymph nodes.  This approach
measures the amount of contrast medium accumulating
within a node versus time after bolus intravenous contrast
administration, and evaluates alterations in nodal microcirculation.
Compared with a normal node, a metastatic node
has a longer time-to-peak accumulation of contrast medium,
a reduced peak enhancement, a reduced slope of accumulation,
and a reduced washout slope. Diffusion-weighted MRI
has been investigated for characterizing cervical adenopathies
based on the hypothesis that nodal metastases may be associated
with alterations in water diffusivity and microcirculation.
The apparent diffusion coefficient (ADC) for cancerous nodes
is reported to be greater than that for benign nodes, which in
turn is greater than that for lymphomas .
A novel MR contrast agent, known as ultrasmall superparamagnetic
particles of iron oxide (USPIO), is classified as a
nanoparticle composed of an iron oxide core. These nanoparticles
have been employed to improve the ability of MRI
to differentiate metastatic from benign nodes. Evaluation with
USPIO requires 2 MR scans performed 24 hours apart. The
first scan is used to identify the location of the lymph nodes.
Twenty-four hours after injection of USPIO, a second MR scan
is performed to evaluate the patterns of contrast enhancement
of the identified lymph nodes .
With intravenous administration of USPIO, a normal node
will phagocytize the particles and the entire node “blackens”
on T2- and T2-weighted images obtained 24 h later. If a part
of the node is infiltrated with tumor, such an intranodal area does not uptake USPIO and, hence, does not blacken.
While CT and MRI have been more widely employed, and
produce a comprehensive assessment of the neck in a single
examination, US has an advantage over these other imaging
techniques by its low cost, ease of use and excellent patient
safety profile as it is noninvasive and avoids exposure to ionizing
radiation. Because it can easily be used to direct a cytologic
examination, US combined with fine-needle aspiration are
gaining popularity. US has not, however, received universal acceptance
because it is highly operator dependent and requires
considerable training. To obtain a high sensitivity, suspicious
lymph nodes with abnormal echogenicity, even as small as 4–5
mm, in the first two echelons should be aspirated. Van den
Brekel et al.  found that in experienced hands the use of
US-guided fine-needle aspiration cytology resulted in a sensitivity
of 76% with a specificity of 100% in N0 necks.
Positron emission tomography (PET) with fluorodeoxyglucose
(FDG) is increasingly used in preoperative staging of cancer
patients. FDG depicts the increased metabolism of malignant
cells as compared with normal cells. The PET scan is therefore
a functional imaging technique based on a combination
of advanced detection equipment and the use of radioactive
tracers. Reports on the value of FDG-PET in detecting occult
metastatic disease have been contradictory with a reported
sensitivity ranging from 0% to 100% and specificity from 92%
to 100% [50,52,53].
Ultrasound-guided fine-needle aspiration can provide cytologic
analysis from nodes as small as 5 mm in diameter. It is
a very accurate method for determining cervical metastasis,
with a reported sensitivity of 90% and specificity of 100%. 
De Bondt et al.  performed a meta-analysis comparing ultrasonography
(US), US guided fine needle aspiration cytology
(USgFNAC), computed tomography (CT), and magnetic
resonance imaging (MRI) in the detection of lymph node
metastases in head and neck cancer. They found that ultrasound-
guided fine-needle aspiration cytology (USgFNAC)
showed to be the most accurate imaging modality to detect
cervical lymph node metastases. Ultrasound also performs
well, whereas computed tomography and magnetic resonance
imaging are less accurate.
Sentinel lymph node biopsy (SLNBX)
The sentinel node concept states that the spread of a tumor
is embolic in nature, via the lymphatics to the first echelon
lymph node(s) encountered in the regional draining basin.
These represent the lymph nodes most likely to harbor occult
metastases, and are designated the sentinel lymph nodes
Excisional biopsy and pathological evaluation of the SLNs
therefore allows for prediction of the disease status of the remaining
cervical lymph node basin, potentially avoiding the
need for a neck dissection. Sentinel lymph nodes need not be
those closest to the tumor, and there may be multiple SLNs.
With the application of early dynamic lymphoscintigraphy,
lymphatic channels are usually visualized, and nodes on a
direct drainage pathway may be distinguished. The practical
approach may include the combination of available detection techniques. The SN procedure consists of three steps: identification,
surgical removal, and extensive Histopathological
evaluation of the SN. Identification of the SN is possible after
peritumoural injection of a radiopharmaceutical (referred to
as tracer). In Europe, mainly 99mTc-Nanocoll is used as tracer,
but also other tracers have been used. The tracer consists of
a colloid labeled to the gamma emitting radioisotope 99mTc.
The tracer is followed during migration, and uptake of the
tracer in the first draining lymph node (the SN) is currently
visualized by using a gamma camera or SPECT/CT (referred
to as lymphoscintigraphy). The localization of the identified
SN is marked on the skin. Surgical removal of the SN via a
small incision is performed under handheld gamma probe
guidance and, optionally, blue dye guidance. Of note, most
centers perform the lymphoscintigraphy one day prior to surgery.
The final step of the procedure is extensive Histopathological
examination of the SN using step-serial sectioning and
Immunohistochemical staining .
Gould et al.  reported the indication of neck dissection for
parotid cancer using the word ‘‘sentinel lymph node’’ in 1960.
They were surprisingly prescient to have foreseen the sentinel
node concept of head and neck cancer more than 40 years ago.
In 1977, Cabanas  described the sentinel node concept of
penile cancer. Recently, many investigators in the head and
neck field have been studying and reporting sentinel lymph
node (SLN) localization and biopsy [55, 58-61].
The most important inclusion criterion for SNB is a clinically
negative neck, as defined by physical examination and clinical
imaging by computed tomography (CT), contrast-enhanced
magnetic resonance imaging (MRI), ultrasound-guided fineneedle
aspiration cytology (USg-FNAC), and/or 18F-fluorodeoxyglucose
(FDG) positron emission tomography (PET)
with or without low-dose CT (PET/CT).
The first and most frequent indication for SNB is to stage the
ipsilateral cN0 neck in patients with a unilateral primary tumor.
A second indication is for assessment of bilateral cN0
necks in primary tumors close to, or crossing, the midline.
The third indication is for assessment of the contralateral cN0
neck in primary tumors close to the midline with an ipsilateral
cN? neck, in order to decide whether these patients need
bilateral neck dissections, or an ipsilateral neck dissection and
contralateral SNB only. Patients should also be fit enough preoperatively
to withstand a neck dissection.
Patients who have received prior radiation or surgical treatment
to the neck are routinely excluded from SNB protocols,
since the previous intervention can distort the normal lymphatic
pathways and give rise to unexpected patterns of metastasis.
It is possible that lymphatic mapping and SNB may yield
potentially useful information in these patients. Similarly, patients
with small recurrent or second primary tumors may also
benefit from lymphatic mapping to guide surgical intervention.
However, these applications of the SNB technique, whilst
clinically attractive, remain largely unexplored .
In pregnant women, the urgency and the necessity of staging
the neck should be discussed. Lymphoscintigraphy is specifically
contraindicated in the pelvis of pregnant women, but no
such recommendations are currently available for the head
and neck. The risk of fetal damage is negligible during routine
SNB procedures. However, SNB protocols should be modified
in pregnant patients to minimize risks of radiation exposure
and blue-dye injections. For example, the use of a 1-day protocol
allows a lower injected radiation dose, and the additional
radiation associated with SPECT/CT imaging may not be
warranted in the pregnant patient. SNB can be performed in
lactating women, but it is advised that breastfeeding be discontinued
following the procedure .
Staging of cancers by sentinel lymph node identification and
biopsy is based on the concept that metastasis from a primary
tumor occurs by predictable orderly spread. The first to receive
the metastatic spread will be the first echelon node before filtering
to the remainder of the lymphatic basin. Therefore, identification
and histopathologic examination of the sentinel node
can define the disease status of the entire regional lymphatic
nodal basin. SLNB involves preoperative lymphoscintigraphy,
intraoperative lymphatic mapping using hand held gamma
probe or vital blue dye and finally pathologic evaluation of
the sentinel lymph node. Patients who have N0 head and neck
cancer may benefit most from SLNBX. Approximately 20% to
40% of patients who have N0 disease harbor microscopic tumor
foci. Thus, approximately two thirds of patients who have
N0 head and neck cancer will have no pathologic evidence of
metastatic disease. Taking a ‘‘wait and see’’ approach in patients
with N0 cancer has been associated with disease recurrence
and a worsened prognosis. SLNBX has the potential of
avoiding either overtreatment or undertreatment of the neck.
In addition, SLNBX has the added benefit of improved disease
staging by directing the pathologist to the ‘‘highest risk’’ lymph mornode
or nodes, which may be more extensively evaluated by
either immunohistochemical or molecular techniques .
The sentinel lymph node is likely to be the first lymph node
to harbour metastasis and can be used to provide information
on the rest of the nodal basin. It is usually identified by peritumoral
injection of radioactive colloid and blue dye. Preoperative
lymphoscintigraphy, intra operative visualisation of blue
colouration, and intra operative radionuclide detection with a
gamma probe allow identification of the sentinel lymph node.
After surgical removal, this node is studied meticulously by
histopathological examination, using stepped serial sectioning
and immunohistochemistry .
In summary, SNB is currently indicated for cT1/2, cN0 oral,
and select oropharyngeal SCC, where it may be considered a
valid alternative to elective neck dissection. Other head and
neck sites, histologies, and clinical situations remain under investigation.
Recently, the use of near-infrared (NIR) fluorescent light has
been introduced to intraoperatively identify lymph nodes, tumors
and vital structures. NIR fluorescence using the fluorescent
dye indocyanine green (ICG) has been successfully used
for sentinel lymph node mapping in breast cancer, melanoma,
cervical cancer, and vulvar cancer. [65-68] The concept of NIR
fluorescence guided SLN mapping in oropharyngeal cancer
has also been reported in humans .
Advantages of SLNB; improves the accuracy of tumor staging,
minimally invasive procedure, avoid unnecessary nodal
dissection, and limited morbidity and mortality with negative
predictive value of 90-95%.
Disadvantages includes; unlike small primary tumors, a bulky
invasive primary tumor invades adjacent anatomic subsites
thus posing difficulty for peritumoral injection, proximity of
primary tumor to the draining lymphatic basin, as is seen in
floor of the mouth tumors, clinically positive nodes are difficult
to be identified by sentinel node mapping because of
the poor uptake of tracer; instead they redirect the entire lymphatic
flow. Additional second stage surgery needed in case of
positive neck node .
If proposed as a staging method, SNB should be feasible and
reliable enough to replace elective neck dissection. SNB may
prevent patients from unnecessary neck dissection and thereby
from shoulder morbidity, pain and sensibility disorders
which negatively influence health-related quality of life .
Moreover, if patients are prevented from neck dissection, a
barrier to cancer spread is preserved in case of recurrence or
second primary tumor. If proposed as a lymphatic mapping
method, SNB may assist elective neck dissection by determining
the neck side and levels that should be dissected. As an
assistant in lymphatic mapping, SN identification may also assist
the histopathological examination of the neck dissection
specimen. If SN’s are marked in the specimen, these specific
lymph nodes can be step-serially sectioned and stained by immunohistochemistry
leading to more accurate staging of the
neck by the possibility of detecting more reliable micrometastases
or isolated tumor cells [14,70].
Civantos et al conducted study to compared two surgical techniques for evaluating the cervical lymphatics. The negative
predictive value of SLNB, defined as the proportion of patients
with negative sentinel nodes who were negative with respect to
other nodes in the neck, was 96% for a population of T1 and
T2 oral cancers. For T1 lesions, and for more experienced surgeons,
the negative predictive value was 100%. They concluded
that; it is reasonable to initiate clinical trials involving SLNB,
with completion ND only for patients with positive sentinel
nodes, as a lower morbidity approach for selected patients’
withT1and T2 oral cancers .
In the USA the cost of treating head and neck cancer is significant
when compared with other solid tumors, only surpassed
by lung and ovarian cancer . In Germany and the USA
the estimated cost was €893 million and €1.0 to 1.9 billion per
year respectively , and in France the estimated cost was
€530.5 million , with OSCC contributing 25% to the total.
Per patient the cost of treatment between 1994 and 1996 in
the Netherlands was €25,425 with 10 years follow up where
In 2013, Govers et al.  performed comparative study to assess
the cost-effectiveness of five strategies for diagnosing and
treating cT1–2N0 oral squamous cell cancer. A Markov decision
analytic model was used to evaluate the cost-effectiveness
of elective neck dissection (END), watchful waiting (WW),
gene expression profiling (GEP) followed by neck dissection
(ND) or WW, sentinel lymph node (SLN) procedure followed
by ND or WW, and GEP and SLN (for positive GEP) followed
by ND or WW. Uncertainty was addressed using one-way and
probabilistic sensitivity analyses. Base-case analysis showed
that SLN procedure followed by ND or WW was the most effective
and most cost effective strategy. SLN was found to have
the highest probability (66%) of being cost-effective of the five
Should a patient with a cN0 neck treated now or
wait and see?
There is great controversy regarding the treatment for clinically
negative necks. The protagonists of observation cite the
morbidity of END as a reason to observe. Another argument
for close observation is that with close follow-up, any cervical
metastasis can be detected early and then treated with adequate
therapy. Furthermore, the occult metastatic rate to the
neck from oral cavity cancer is 34%. Hence, it is argued that
nearly two thirds of the patients would be exposed to the mornode bidity of a neck dissection unnecessarily .
A decision-tree analysis was created by Weiss et al  based
on an analysis of the utility of the management options taking
into account the incidence of node involvement, complications
of treatment, and disease control rates. They concluded that
observation is the preferred option when the probability of occult
metastasis is less than 20% and elective neck treatment (irradiation
or dissection) is preferred if the probability of occult
metastasis is greater than 20%. In squamous cell carcinoma of
the oral cavity the sites with a less than 20% occult metastatic
rate to the neck are T1/T2 lip carcinomas, T1/T2 oral tongue
carcinomas that are less than 4 mm thick, and T1/T2 floor of
mouth cancers less than or equal to 1.5 mm thick. Weiss et al
 have however alluded that the values will change and the
threshold will be altered with the times.
On the other hand; the proponents of surgical intervention
also note that removal of lymph nodes can be used as a staging
procedure. If there is presence of extra capsular spread, the
patient can be upstaged and receive more aggressive therapy
early on rather than later when survival may be adversely affected.
Andersen et al.  demonstrated that 77% of patients
with clinically N0 necks at initial observation had pathologically
adverse findings at the time of neck dissection. Furthermore
49% of these patients had ECS, a poor prognostic factor.
Hence, they argued for elective neck treatment (irradiation or
neck dissection) in patients with N0 necks.
The decision to observe or treat the N0 neck is left to the choice
of the patient and the head and neck oncologist, in oral cavity
carcinoma the only clinically N0 necks for which observation
is appropriate are those associated with T1/T2 lip carcinomas,
T1/T2 oral tongue carcinomas that are less than 4 mm thick,
and T1/T2 floor of mouth cancers less than or equal to 1.5 mm
Should the patient receive an elective neck dissection
or should they be treated with elective neck
The issue of the use of elective surgery versus elective radiation
ends not at which treatment modality is more beneficial, but
which one is less harmful. The patient's age, general health,
family support, reliability and patient's own wishes are important.
The reasons for using END are; Neck dissection has low morbidity
& mortality, Cure rate for neck dissection is decreased if
lymph node enlargement occurs or multiple nodes appear. It is
impossible to provide follow-up necessary to detect the earlier
conversion of a neck from N0 to N1, Allowing the neck metastases
to develop increases the incidence of distant metastasis.
If neck has been entered to remove the primary it is better to
perform an in-continuity resection and High incidence of occult
metastatic disease while cons for END are; END results in
a large number of unnecessary surgical procedures and is associated
with inevitable morbidity. Cure rates are no lower if the
surgeon waits for the neck to convert from N0 to N1, Careful
clinical follow-up will allow detection of the earliest conversion
from N0 to N1, END removes the barrier to the spread of
disease and also has a detrimental immunological effect, and Radiation is as effective as neck dissection in N0 neck .
Mendenhall et al.  showed that elective neck irradiation
(ENI) reduced the neck failure rate in patients with controlled
primary tumors and N0 necks from 18% to 1.9%. The dose of
radiation varied from 50 Gy to 75 Gy in the upper neck and
from 40 Gy to 50 Gy in the lower neck will control occult metastases
in 90 to 95% of cases .
Although prospective evidence is lacking, retrospective data
suggest that for most sites and for early lesions, elective nodal
irradiation (ENI) and END offers equivalent local control.
Proponents of ENI assert that the morbidity is low with limited
soft tissue changes and does not have systemic ramifications.
However, considerable acute adverse effects such as mucositis
and xerostomia, together with late effects like endarteritis,
radionecrosis etc .can occur. Systemic effects include suppression
of humoral and cell mediated immunity .
In a trial to get the benefits of END and decrease the morbidity,
Endoscopic neck dissections has been tried. It’s oncological
safety and usefulness in practice are other issues that need to
be addressed .
Are there prognostic factors that can guide us in
our decisions in treating the neck?
Vascular and lymphatic networks, which vary between different
anatomic sites, may influence tumor evolution and the
outcome. Higher metastatic disease rates for SCC at the base
rather than at the oral tongue have been reported .
Leite and Koifman  showed higher mortality rates in patients
with tongue carcinomas than in those who developed lip
carcinomas. In addition, some anatomic sites are linked with
poorer outcome owing to the rich lymphatic drainage and the
local extension being hard to evaluate and manage, such as the
superior gingiva-labial sulcus.  Also, The risk of nodal metastases
and mortality rates vary directly with the thickness of
the primary tumor .
The margin refers to how close the cancer cells are to the edge
of the normal tissue surrounding the tumor. The presence of
residual carcinoma at the margins of surgical resection is an
important risk factor for local recurrence in OSCC. Positive
margins indicated microscopically aggressive tumor biology.
Margins of tumor could also be categorized as follows; Clinical
margins: the margins of tumor on clinical examination
that is on observation and palpation. It was always included
during the surgical removal of tumor tissue. Surgical margins:
The status of the surgical margin was an important predictor
of outcome. The surgical margin, in contrast to the other prognostic
indicators is under the direct control of the surgeon.
Close surgical margins were considered as positive margins.
High correlation existed between histological indicators of aggressive
disease and close or involved surgical margins. These
results implied that close surgical margins in OSCC could be
regarded as an indicator of aggressive disease. Histological
margins: Margins were described in the following three ways;
Positive margins: Invasive tumor within 5 mm of final surgical
margin. Cancer cells were involving the outer edge of tissue.
Carcinoma in situ involved final surgical margin. Dysplasia involved final surgical margin. Negative margins: No cancer cells
were seen at the outer edge. The standard negative measurement
in most hospitals is 2 mm of normal tissue beyond the
edge of the tumor. Close margins: Cancer cells were very nearby
but did not involve the outer edge of tissue. Close margin lie
between positive and negative margins . Local recurrence
rate, ranged from 64 to 84% for positive margins. The presence
of positive margins predicted poor overall survival for oral
cancer. Intraoperative use of frozen sections for determining
margin status reduced the local recurrence. Patients with clear
margins had a survival rate of 69% at 5 years compared to 58%
with close and 38% with involved margins. Intraoperative use
of frozen sections for determining margin status also reduced
the local recurrence.
Molecular margins: With advanced technology like the use of
molecular markers to predict the positivity of tumor front or
outer edges of the excised tissue. It has actually proved to be
an ideal method to determine the adequacy or extent of tumor
tissue removal. Various molecular markers could also be utilized
for this purpose .
Infiltration of perineural spaces occurs in up to 52% of OSCC.
Mediated through Nerve Cell Adhesion Molecule (NCAM),
on the surface of cancer cells which engage in homophilic
binding with NCAM receptors (expressed by neural and perineural
tissue) . The presence of Perineural Invasion (PI) in
primary tumor is a predictor for cervical metastasis, locoregional
recurrence. Centripetal and centrifugal propagation of
tumor cells along perineural spaces and away from primary
tumor is responsible for local recurrence . Most tumors allow 2 centimeter (cm) of dissemination of tumor cells along
perineural space, so malignant cells that evade surgical excision
and radiotherapy, results in local recurrence. The relationship
between PI and prognosis is independent of nerve diameter,
so in all cases of OSCC, the pathological specimen should
be examined for PI even in nerves less than 1 mm in diameter.
Vascular invasion is defined as, “the presence of neoplastic
cells within an endothelial cell lined channel.” It occurs in
more than 50% of head and neck squamous cell carcinomas. It
correlates with the presence of concomitant cervical metastases
and showed an increased risk of distant metastatic disease
. The skin of face and scalp is most commonly affected by
metastases, suggesting that blood vessels and patterns of innervations
may influence the spread of metastases .
Which modality should be used for treating the
Treatment modality of the primary cancer plays an important
role in the decision as to how to treat the neck. If primary
radiation therapy is used, ENI can be performed. If the neck
is going to be entered to remove the primary tumor, an END
can be performed. Obviously, the risks of ENI and END need
to be considered on an individual basis for each patient. The
most important factors in guiding this decision should be the
patient’s informed decision, physician and institution experience,
risk of second primary occurrence in the future, and the
modality chosen to treat the primary cancer. The results of our
systematic review showed that, the total number of patients
treated by neck dissection is 2291 with failure or recurrence
in 148 patients and patients treated by wait and see policy is 1523 with failure or recurrence in 406, while patients treated
by combined therapy were 42 and failure or recurrence in 9 patients.
Radiotherapy was used in only 11 patients with failure
or recurrence in 6 patients (Figure 2).
What are the future trends?
Current assessment of lymph node metastasis in patients with
head and neck squamous cell carcinoma is not accurate enough
to prevent overtreatment. Previous studies have indicated that
gene expression profiling can potentially help predict lymph
node status in HNSCC and OSCC, in particular [93-95]. Such
a signature [96,97] is completely independently verified in this
large multicenter study that was performed in a CLIA/ISO–
certified laboratory using a diagnostic array platform. The results
indicate that the signature should be prospectively tested
and applied alongside current clinical assessment to identify
a subgroup of patients with OSCC for whom a watchful waiting
strategy would be appropriate. Combining current clinical
assessment with the expression signature would decrease the
rate of undetected nodal metastases from 28% to 11% in earlystage
OSCC. This should be sufficient to enable clinicians to
refrain from elective neck treatment. A new clinical decision
model that incorporates the expression signature is therefore
proposed for testing in a prospective study, which could substantially
improve treatment for this group of patients .
Risk stratification is important in cancer treatment because it
provide information that may be used to select the most appropriate
therapeutic approach. Several well-known Risk stratification
systems are applied worldwide today [99,100]. Other
Risk stratification systems based on prognostic factors also assist
physicians to more confidently select treatment strategies;
furthermore, they facilitate the selection of more homogenous
patients groups for clinical trials [101, 102].
In conclusion, this systematic review revealed that, among the
OSCC patients with cN0 neck dissection seem to be superior
to the others treatment policies, followed by wait and see policy
in terms of survival and control of neck disease. Sentinel
lymph node biopsy seem to be superior to Ultrasonographyguided
cytology in terms of diagnostic accuracy and postoperative
recurrence or failure. SLN biopsy could potentially guide
head and neck oncologists to the patient with N0 disease who
would benefit most from selective neck dissection and prevent
the morbidity of unnecessary neck dissection.
In comparison with US, CT & MRI, it seems that the USgFNAC
is the most reliable imaging technique to assess the
presence of metastases in cervical lymph nodes in patients
with head and neck cancer.
Conflict of interest
None of the authors has any conflict of interest, financial or