Oral Cavity Cancer

Kyle S. Ettinger, MD, DDSa,b, Laurent Ganry, MDb,c,

Rui P. Fernandes, MD, DMDd,*

KEYWORDS
 Oral cavity cancer  Squamous cell carcinoma  AJCC staging  NCCN guidelines
 Depth of invasion  Maxillofacial surgery  Anatomic subsite  Neck dissection

KEY POINTS
 There have been several significant changes made to the recently released American Joint Com-
mittee on Cancer eighth edition of the AJCC Cancer Staging Manual and the 2018 National
Comprehensive Cancer Network management guidelines for oral cavity carcinoma that all maxillo-
facial surgeons should have a comprehensive foundational knowledge of.
 New pathologic parameters, such as depth of invasion, now provide objective criteria for surgeons
to gauge the necessity of performing elective neck dissection for early-stage clinically node-
negative oral cavity carcinomas.
 The breadth of available literature supports differing clinicopathologic behaviors of squamous cell
carcinomas arising from different anatomic subsites within the oral cavity.
 The relationship between subsite-specific risk of occult nodal metastasis and pathologic depth of
invasion has yet to be definitively clarified within the current management guidelines for oral cavity
squamous cell carcinoma.
 Locoregional management considerations for oral cavity squamous cell carcinomas are inherently
unique to a primary tumor’s subsite of origin, and a thorough understanding of these considerations
remains critical to successful oncologic and reconstructive outcomes.

INTRODUCTION the oral cavity.2 As recently as 2003, oral cavity

Squamous cell carcinoma represents the most
common form of head and neck cancer—
comprising approximately 90% of all head and
neck malignancies.1 Squamous cell carcinomas
can arise from all parts of the upper aerodigestive
tract, including the nasopharynx, lip, oral cavity,
oropharynx, hypopharynx, and larynx. Of all the
anatomic sites within the head and neck, squa-
mous cell carcinomas most commonly arise within
squamous cell carcinoma (OSCC) was the eighth
most common cancer worldwide.3 More recently,
OSCC has climbed to the sixth most common
global malignancy as of 2016.4 Unlike the treat-
ment of cancer arising from other anatomic sites
of the head and neck, the primary treatment
strategy for OSCC remains surgery. Although
multimodal therapy, including adjuvant radiation
therapy (RT) with or without chemotherapy, is

Disclosure Statement: The authors have nothing to disclose.

a
Division of Oral and Maxillofacial Surgery, Department of Surgery, Section of Head and Neck Oncologic Sur-
oralmaxsurgery.theclinics.com

gery and Reconstruction, Mayo Clinic, Mayo College of Medicine, Mail Code: ro_ma_12_12econ, 200 First
Street Southwest, Rochester, MN 55905, USA; b Department of Oral and Maxillofacial Surgery, Division of
Head and Neck Surgery, University of Florida College of Medicine – Jacksonville, 653-1 West 8th Street 2nd
FL/LRC, Jacksonville, FL 32209, USA; c Department of Maxillo-facial, Plastic, Reconstructive and Aesthetic Sur-
gery, Henri Mondor Hospital, 51 avenue du Maréchal de Lattre de Tassigny, Créteil 94010, France; d Division of
Head and Neck Surgery, Head and Neck Oncologic Surgery and Microvascular Reconstruction Fellowship,
Department of Oral and Maxillofacial Surgery, University of Florida College of Medicine – Jacksonville, Univer-
sity of Florida – Jacksonville, 653-1 West 8th Street 2nd FL/LRC, Jacksonville, FL 32209, USA
* Corresponding author.
E-mail address: rui.fernandes@jax.ufl.edu

Oral Maxillofacial Surg Clin N Am - (2018) -–-

https://doi.org/10.1016/j.coms.2018.08.002
1042-3699/18/Ó 2018 Elsevier Inc. All rights reserved.
2 Ettinger et al
frequently used for advanced-stage disease, sur-
gery remains the cornerstone in the management
of OSCC. Therefore, oral and maxillofacial sur-
geons must remain apprised of the current
practice guidelines and evidence supporting
the locoregional management of OSCC. Accord-
ingly, this article summarizes the most the recent
changes to staging and management guidelines
for OSCC and reviews specific considerations for
surgery involving various anatomic subsites within
oral cavity.
The American Joint Committee on Cancer
(AJCC) and National Comprehensive Cancer
Network (NCCN) are 2 of the most authoritative
sources for oral and maxillofacial surgeons
on the current standards of practice and for rec-
ommendations on the management of OSCC.
Recently released updates on the consensus rec-
ommendations include important changes for both
the staging and the locoregional management of
OSCC.
AMERICAN JOINT COMMITTEE ON CANCER
STAGING FOR ORAL CAVITY SQUAMOUS
CELL CARCINOMA
Changes to the TNM System of the Eighth
Edition of the American Joint Committee on
Cancer
The TNM classification of malignant tumors is the
most widely used system for cancer staging within
the United States and internationally. The system
not only serves as a common language among
providers of differing specialties who collaborate
in the multidisciplinary treatment of cancer pa-
tients but also guides management and provides
prognosis based on population data. The most
recent release of the eighth edition of the AJCC
Cancer Staging Manual has presented significant
changes to the TNM staging system for OSCC.5
The most notable changes include
 Incorporation of depth of invasion (DOI) into T
staging
 Elimination of the T0 category
 Minor modification to features of the T4a
category
 Incorporation of extranodal extension (ENE)
into the regional lymph node N staging
 Addition of subclassifications to the N3
category
The purpose of the changes is to improve haz-
ard discrimination for more accurate prediction
of prognoses and outcomes of patients by the
AJCC staging system. Comparisons between the
seventh edition of the AJCC Cancer Staging
Manual6 and eighth edition of the AJCC Cancer
Staging Manual5 for OSCC T categories and N cat-
egories can be found in Tables 1 and 2.
Depth of Invasion
The incorporation of DOI into the T staging of
OSCC represents a significant and perhaps argu-
ably overdue advance in the TNM system of the
most recently published eighth edition of the
AJCC Cancer Staging Manual. Tumor growth
pattern and overall tumor dimension are increas-
ingly recognized as features critical to assessing
tumor behavior and to determining the most
optimal locoregional management.7–11 Oncologic
surgeons have long recognized, even if anecdot-
ally, that small but deeply invasive endophytic tu-
mors often portend a much more aggressive
clinical and biologic course compared with even
very large tumors with more outwardly expanding
exophytic growth patterns. By incorporating DOI
into the routine T staging of OSCC, DOI has
been differentiated from other histologic measure-
ments, such as “tumor thickness,” which has long
been used imprecisely as an interchangeable term
for DOI. In response, the AJCC has issued explicit
instructions for measuring DOI in the eighth edition
of the AJCC Cancer Staging Manual. Microscopic
measurement of DOI should begin from a
horizontal line at the basal layer of the closest his-
tologically normal appearing squamous epithelium
adjacent to the tumor and extend along a perpen-
dicular plum line to the deepest point of tumor in-
vasion (Fig. 1). The distance measured from the
horizon line to the deepest point on the plumb
line is the pathologic DOI of the tumor. DOI is
distinct from tumor thickness, which is the
maximal dimension of the tumor at its thickest
point, irrespective of the relationship of the
tumor to the uninvolved adjacent epithelium. The
distinction between DOI and tumor thickness for
endophytic versus exophytic growth patterns is
highlighted in Fig. 2.
The eighth edition of the AJCC staging system
incorporated clinical as well as pathologic DOI
into the T staging of OSCC (see Table 1). Accurate
clinical staging relies on physical examination by
palpation of the primary tumor and surrounding
tissues for induration or fixation to underlying
structures that suggest a more deeply invasive
growth pattern. For tumors close to bone, preop-
erative imaging studies should be carefully
assessed for signs of bone erosion that portend
invasive growth patterns (T4a).
In the updated eighth edition, DOI for T staging
of OSCC is classified by increasing increments of
5 mm. Less-invasive tumors are classified by DOI
less than or equal to 5 mm, moderately invasive

Table 1
Changes from the seventh edition to the eighth edition of the AJCC Cancer Staging Manual: T category
for oral cavity squamous cell carcinoma
American Joint Committee on Cancer Seventh
Edition
T Category T Criteria
Tx Primary tumor cannot be assessed
T0 No evidence of primary tumor
Tis Carcinoma in situ
T1 Tumor 2 cm in greatest dimension
T2 Tumor >2 cm but 4 cm in greatest
dimension
T3 Tumor >4 cm in greatest dimension
T4a Moderately advanced local disease
Lip: tumor invades through
cortical bone, inferior alveolar
nerve, FOM, or skin of face (ie,
chin or nose)
Oral cavity: tumor invades
adjacent structures only (ie,
through cortical bone,
[mandible or maxilla], into deep
[extrinsic] muscles of tongue
[genioglossus, hyoglossus,
palatoglossus, and styloglossus],
maxillary sinus, skin of face)
T4b Very advanced local disease
Tumor invades masticator space,
pterygoid plates, or skull base and/
or encases internal carotid artery
Adapted from Amin MB, American Joint Committee on Cancer. AJCC cancer staging manual. 8th edition. New York:
Springer; 2017; and Edge SB, American Joint Committee on Cancer. AJCC cancer staging manual. 7th edition. New
York: Springer; 2010.
tumors are classified by DOI greater than 5 mm
and less than or equal to 10 mm, and deeply inva-
sive tumors are classified as DOI greater than
10 mm. By stratifying for DOI in the eighth edition,
tumors with increasing levels of DOI are upstaged
from the previous edition that considered tumor
size alone in determining T stage for OSSC. For
instance, a 1.5-cm tumor with a DOI of 4 mm is
staged T1; whereas a 1.5-cm tumor with 6 mm
DOI is now staged T2. Staging by the eighth edi-
tion thus discriminates different stages for these
2 tumors that would have been assigned the
same T1 stage in the seventh edition. Although
the incorporation of DOI into the eighth edition
for T staging results in a slightly more complicated
system, vetting of the eighth edition T-staging
criteria within registry-level data has demonstrated
improved hazard discrimination in overall survival
among patients previously treated for OSCC
Oral Cavity Cancer 3
American Joint Committee on Cancer Eighth
Edition
T Category T Criteria
Tx Primary tumor cannot be assessed
Tis Carcinoma in situ
T1 Tumor 2 cm, DOI 5 mm
T2 Tumor 2 cm, DOI >5 mm and
10 mm or tumor >2 cm but 4 cm
and DOI 10 mm
T3 Tumor >4 cm or any tumor
DOI >10 mm
T4a Moderately advanced local disease
Lip: tumor invades through
cortical bone or involves the
inferior alveolar nerve, FOM, or
skin of face (ie, chin or nose)
Oral cavity: tumor invades
adjacent structures only (that is,
through cortical bone of
mandible or maxilla, involves
the maxillary sinus, or skin of the
face
T4b Very advanced local disease
Tumor invades masticator space,
pterygoid plates, or skull base and/
or encases internal carotid artery
primaries.5 Thus, patients with more deeply inva-
sive tumors carry a worse prognosis relative to pa-
tients with similarly sized primary tumors and
lesser DOI who were previously understaged by
the criteria of the seventh edition.12
Elimination of the T0 Category from Oral
Cavity Squamous Cell Carcinoma
Under all preceding head and neck AJCC staging
systems, the T0 category was reserved for clinical
scenarios in which regional lymph nodes were
found by biopsy as harboring metastatic carci-
noma, yet no identifiable primary tumor was found
on clinical examination, imaging review, or
directed biopsy of likely primary tumor sites.
More than 90% of unknown primaries (T0) within
the head and neck, however, have been
shown more recently to have arisen from human
4 Ettinger et al
Table 2
Changes from the seventh edition to the eighth edition of the AJCC Cancer Staging Manual: N category
for oral cavity squamous cell carcinoma
American Joint Committee on Cancer Seventh
Edition
N Category N Criteria
Nx Regional lymph nodes cannot be
assessed
N0 No regional lymph node metastasis
N1 Metastasis in single ipsilateral lymph
node 3 cm in greatest dimension
N2a Metastasis in single ipsilateral lymph
node >3 cm but 6 cm in greatest
dimension
N2b Metastasis in multiple ipsilateral
lymph nodes, none >6 cm in
greatest dimension
N2c Metastasis in bilateral or
contralateral lymph nodes,
none >6 cm in greatest dimension
N3 Metastasis in a lymph node >6 cm in
greatest dimension
Adapted from Amin MB, American Joint Committee on Cancer. AJCC cancer staging manual. 8th edition. New York:
Springer; 2017; and Edge SB, American Joint Committee on Cancer. AJCC cancer staging manual. 7th edition. New
York: Springer; 2010.
papilloma virus (HPV)-associated oropharyngeal
squamous cell carcinomas (OPCs).13,14 In most
centers, immunohistochemistry (IHC) for tumor
suppressor protein p16 serves as the preferred
surrogate biomarker for HPV-associated OPC
due to low cost, universal availability, and ease
of histopathologic interpretation for a definitive
diagnosis. Because few squamous cell carci-
nomas from other anatomic sites outside the
oropharynx are associated with HPV, p16 positiv-
ity on IHC staining should be confirmed by in situ
hybridization (ISH) for these tumors. Thus, p16
positivity on IHC and subsequently confirmed by
ISH for direct detection of high-risk HPV supports
a primary site of origin in the oropharynx for
metastatic carcinoma when clinical examination,
American Joint Committee on Cancer Eighth
Edition
N Category N Criteria
Nx Regional lymph nodes cannot be
assessed
N0 No regional lymph node metastasis
N1 Metastasis in single ipsilateral lymph
node, 3 cm in greatest dimension
and ENE-negative
N2a Metastasis in single ipsilateral or
contralateral lymph node 3 cm in
greatest dimension and ENE-
positive or metastasis in single
ipsilateral lymph node >3 cm but
6 cm in greatest dimension and
ENE-negative
N2b Metastasis in multiple ipsilateral
lymph nodes, none >6 cm in
greatest dimension and
ENE-negative
N2c Metastasis in bilateral or
contralateral lymph nodes,
none >6 cm in greatest dimension
and ENE-negative
N3a Metastasis in lymph node >6 cm in
greatest dimension and ENE-
negative
N3b Metastasis in single ipsilateral lymph
node, >3 cm in greatest dimension
and ENE-positive or metastasis in
multiple ipsilateral, contralateral
or bilateral lymph nodes, with any
ENE-positive
endoscopy, and imaging are equivocal. Likewise,
nasopharyngeal carcinoma is yet another virally
associated head and neck cancer that may mani-
fest with regional nodal disease in the absence of
an identifiable primary tumor at the expected
mucosal site of origin. Modern ISH techniques
readily detect Epstein-Barr virus RNA in a vast ma-
jority of nasopharyngeal carcinomas presenting
with an occult primary. Similarly, clinicians may
accurately determine the primary site in the naso-
pharynx for a metastatic regional lymph node
demonstrating Epstein-Barr virus biomarker posi-
tivity.15 Therefore, the eighth edition of the AJCC
staging system reserves the T0 designation for
HPV-associated OPCs, nasopharyngeal carci-
nomas, and salivary gland carcinomas.5

Fig. 1. Measurement of pathologic DOI (hematoxylin-
eosin, original magnification  100). A horizon line is
established from the basement membrane of the
closest adjacent normal squamous epithelium (white
arrow). A plumb line is then dropped from the hori-
zon line to the deepest point of tumor invasion. The
length of the plumb line corresponds to pathologic
DOI.
Changes to N-Staging Criteria
One of the most salient changes made to the
AJCC eighth edition for N staging is the incorpo-
ration of pathologic ENE. Like the incorporation
of DOI into the staging of OSCC, the addition of
ENE into the N category reflects the prognostic
significance of ENE on clinical outcomes and
further improved hazard discrimination. Identi-
fying ENE upstages the pathologic N category
by 1 level in the revised eighth edition criteria.
The traditional lymph node size intervals of less
than or equal to 3 cm, greater than 3 cm but
less than or equal to 6 cm, and greater than
6 cm remain unchanged relative to their respec-
tive N1, N2, and N3 categories; however, the
incorporation of ENE subtly changed the impact
of isolated ipsilateral or contralateral nodal
involvement within the N2a category while adding
a subclassification of the N3 category (see
Table 2). In the seventh edition, involvement of
a contralateral lymph node was staged pN2c,
whereas a single ipsilateral or isolated contralat-
eral lymph node that is less than or equal to
3 cm but ENE-positive is staged pN2a in the
eighth edition. Additionally, any lymph node
greater than 3 cm but less than or equal to
6 cm previously was staged pN2 but with ENE
is staged pN3b by the eighth edition. Lymph
nodes greater than 6 cm, previously staged
pN3, and without ENE are staged pN3a in the
eighth edition—thus further refining hazard
discrimination and reflecting the better prognosis
and outcome for patients without ENE in meta-
static lymph nodes. Clinicians also should be
Oral Cavity Cancer 5
Fig. 2. DOI versus tumor thickness (hematoxylin-eosin,
original magnification  100). (A) In this predomi-
nantly exophytic tumor, the maximal tumor thickness
(white line) is markedly greater than the DOI (black
plumb line). (B) In this predominantly endophytic ul-
cerative tumor, the DOI (black plumb line) is decep-
tively greater than the maximal tumor thickness
(white line). These examples highlight how tumor
thickness can overestimate (for exophytic tumors) or
underestimate (for endophytic tumors) potential tu-
mor aggressiveness compared with DOI.
aware of the recommendation in the eighth edi-
tion that for preoperative clinical staging of the
neck, ENE is affirmed only with obvious evidence
of physical examination findings, such as skin
invasion, infiltration of musculature, dense teth-
ering of adjacent structures, cranial nerve,
brachial plexus, phrenic nerve, and sympathetic
trunk dysfunction. Clinical suspicion of ENE
must also be supported by findings on imaging
that suggest ENE for valid use in preoperative
clinical staging.
2018 NATIONAL COMPREHENSIVE CANCER
NETWORK MANAGEMENT GUIDELINES FOR
ORAL CAVITY SQUAMOUS CELL CARCINOMA
The NCCN Clinical Practice Guidelines for can-
cers of the head and neck were recently updated
6 Ettinger et al

in February of 2018.16 Like previous iterations of
the NCCN Guidelines, the preferred primary
treatment of OSSC remains surgery. Although
primary treatment with RT alone or concurrent
chemoradiation therapy (chemo-RT) have
advanced the management of squamous cell car-
cinoma arising from sites outside of the oral cav-
ity,16 definitive surgery remains the foundation of
any approach with curative intent in the manage-
ment of OSCC. This is largely because essentially
all early-stage and even most advanced-stage
OSCCs are amenable to surgical resection.
With advances in modern microvascular recon-
struction, patients with OSCC can undergo
simultaneous tumor ablation and immediate
reconstruction with optimal functional and
cosmetic outcomes obtained. For early-staged
disease, surgery alone may be adequate initial
treatment of OSCC, sparing adjuvant radio-
therapy with the associated long-term sequelae
and morbidity. Nonetheless, for most patients
with intermediate-staged to advanced-staged
disease, adjuvant radiation alone or chemoradia-
tion is indicated to reduce the risks of local and
regional recurrence.
The role for adjuvant therapy in the treatment
of OSCC is based on the pathologic T staging
and N staging after resection of the primary tu-
mor and dissection of the neck lymph nodes at
risk for metastasis. RT alone or combined with
chemotherapy is indicated as adjuvant therapy
for advanced-stage disease, for the presence
of adverse pathologic features, and for patho-
logically identified regional nodal metastasis.
The indications for adjuvant therapy remain
largely unchanged in the 2018 update of the
NCCN management guidelines and should be
familiar to surgeons as standards of practice
(Table 3).16
National Comprehensive Cancer Network
Management Recommendations for the N0
Neck
Although the oncologic principles for resection of
the primary tumor for OSCC are generally
agreed on, ongoing debate continues on how to
most appropriately manage the neck—particu-
larly among patients with no evidence of regional
disease. The presence of regional metastatic dis-
ease is the most significant indicator of prognosis
and decreases survival rates for head and neck
cancer by 50%. Approximately 30% of clinically
node-negative (cN0) patients harbor occult nodal
metastasis that is undetectable by routine clinical
and radiographic examination.17 The recommen-
dation for elective neck dissection (END) for pa-
tients staged cN0 has historically been based
on the probability of occult nodal metastasis
risk exceeding 20%,18 considering clinicopatho-
logic parameters, such as anatomic subsite of
origin, tumor biomarkers, radiologic findings,
and overall tumor dimensions.19 Imprecision in
determining the risk of occult nodal metastasis
in patients staged cN0 has led to considerable
variability among head and neck surgeons in
managing the neck. A growing body of evidence,
however, supports DOI of the primary tumor as
highly predictive of the risk of occult nodal me-
tastases and aggressive biologic behavior.7–11
Therefore, current management of the neck is
supported by evidence to guide more uniform

Table 3
Adjuvant therapy indications for oral cavity cancer based on 2018 National Comprehensive Cancer
Network management guidelines

Types of Adjuvant Modalities and Associated Indications

RT Chemo-RTa Consideration of either RT or chemo-RTb
 pT1–pT2 with N1  Any ENE  pT1 or pT2, N0 with positive margin and re-resection
nodal disease  pT1-pT2, N1-3 with not possible
positive margin  pT3-pT4a primary
 pT3-pT4a with  N2-N3 nodal disease
positive margin  Nodal disease in levels IV or V of neck
 Perineural invasion
 Lymphovascular invasion
a
The indications listed in this category are based on high-level evidence supporting a uniform consensus from the NCCN
that chemo-RT is the most appropriate treatment strategy for the respective indications.
b
The indications listed in this category are based on lower-level evidence and although there is uniform NCCN consensus
regarding the recommendations, considerations can be made for either intervention.
Data from National Comprehensive Cancer Network. Head and neck cancers (Version 1.2018). NCCN clinical practice
guidelines in oncology. Available at: www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf. Accessed April
1, 2018.

management of early-stage cN0 disease. The
recent changes of both the AJCC Cancer Staging
Manual and NCCN Guidelines have added DOI of
the primary tumor to guide management of the
regional nodal basins for patients with no clinical
or radiologic evidence of disease. The NCCN
provides the following guidelines for END in
early-stage cT1-T2 N0 OSCC16:
 DOI greater than 4 mm—END strongly recom-
mended if RT is not already planned
 DOI less than 2 mm—END is only indicated in
selective situations
 DOI 2 to 4 mm—clinical judgment (consid-
ering patient reliability of follow-up, clinical
suspicion, and other factors) must be used
to determine appropriateness of ion
 Recent randomized trial evidence supports
the effectiveness of END in patients with oral
cavity cancers greater than 3-mm DOI.
Although the current NCCN Guidelines recom-
mend END based on DOI of the primary tumor in
cT1-T2 N0 OSCC, no specific recommendations
are made based on the oral cavity subsite of the
primary tumor. The variability between subsites
of the oral cavity in predicting nodal metastasis
with DOI of the primary tumor has been recognized
for OSCC.20–22 Therefore, some investigators
advocate management of the neck should be
based on unique DOI thresholds specific to
various primary tumor subsites within the oral cav-
ity.7 The primary tumor subsite for OSCC has long
been used by surgeons as a factor to estimate the
risk of occult nodal metastasis and to guide the
decision for END in cN0 patients. Although mea-
surements of DOI provide surgeons with objective
criteria on which to base the decision about
END for cN0 disease, no recommendations for
predicting occult metastasis at specific subsites
in the oral cavity based on DOI are currently in
acceptance.
Some differences should be noted between the
recommendations for END based on DOI of the
primary tumor in the NCCN Guidelines and the
staging of the primary tumor in the eighth edition
of the AJCC Cancer Staging Manual for OSCC.
According to current NCCN Guidelines, END is
recommended for primary tumors with DOI
greater than 4 mm (with some evidence suggest-
ing that 3-mm DOI is supported for oral cavity
cancers).16 The AJCC, however, currently stages
a primary tumor with DOI of less than or equal to
5 mm in the T1 category, with pathologic up-
staging to a T2 category for tumors with
DOI greater 5 mm and less than 10 mm. There-
fore, based on the current NCCN Guidelines,
Oral Cavity Cancer 7
END is indicated even in scenarios that the
AJCC eighth edition considers minimally invasive
T1 lesions with a DOI of less than or equal to
5 mm. Prior clinical practice patterns of observa-
tion of the neck after resection of T1 primary tu-
mors with limited DOI may then conflict with
recommendations of the AJCC Cancer Staging
Manual and NCCN Guidelines. Nevertheless, bet-
ter hazard discrimination of outcomes has been
shown for incorporation of pathologic factors,
such as DOI and ENE, into the stage groupings
of the eighth edition in registry-level data.23
Thus, more standardization of oncologic practice
patterns for management of cN0 disease is
promising.
Accurate assessment of DOI prior to END for
cN0 disease remains largely dependent on the
surgeon and the available resources at their
respective institution. The AJCC and NCCN do
not provide stipulations on the timing or method-
ology of assessing DOI prior to undertaking surgi-
cal interrogation of the neck. Although DOI
assessments can occasionally be garnered from
the initial diagnostic biopsy of the primary tumor,
the method of tumor sampling (ie, incisional vs
excisional), the location of the biopsy (ie, periph-
eral vs central), and depth of biopsy can all influ-
ence the accuracy of the DOI assessment.
Accordingly, some providers may elect to perform
complete tumor resection and use intraoperative
fresh frozen section to more accurately assess
the true pathologic DOI of the entire specimen
prior to dissection of the neck. Depending on
the institutional availability of frozen section tech-
niques, however, this use of approach may not be
feasible for all providers. Therefore, a careful clin-
ical assessment of the primary tumor extent by
meticulous palpation and radiographic examina-
tion can guide surgeons in their presurgical
assessment of a tumor’s anticipated pathologic
DOI and thus the need for END.
National Comprehensive Cancer Network
Recommendations for Sentinel Lymph Node
Biopsy
In 2014, the NCCN Guidelines recommended
sentinel lymph node biopsy (SNB) as an alternative
to END for early-stage cT1-T2 N0 OSCC. The
recommendation was supported by a growing
body of evidence suggesting comparable survival
outcomes between SNB and END24–27 whereas
numerous studies demonstrating consistent accu-
racy and reliability in detecting sentinel nodes
for oral cavity primary tumors.28–34 With the
steep learning curve of implementing the tech-
nique of SNB as a significant obstacle to wide
8 Ettinger et al
acceptance,25 however, the NCCN recommends
the technique only for centers with expertise in
the use of routine staging for patients with early
cN0 OSCC. Additionally, the accuracy SNB for
OSCC is heavily dependent on the proximity of
the primary tumor to the nodal basin, particularly
for floor of mouth (FOM) tumors in which radio-
tracer shine-through can prevent detection of a
sentinel lymph node.27,35,36 Alhough not a univer-
sally demonstrated phenomenon,33,34 the NCCN
Guidelines continue to recommend caution in the
applying SNB for specific anatomic subsites of
the oral cavity that are not amenable to the nu-
ances of the technique.16 A change to the recom-
mendations for SNB in 2018 NCCN Guidelines is
the use of the technique in the preferred clinical
treatment pathway of early-stage cT1-T2 N0
OSCC,16 whereas prior iterations maintained the
technique as a separate clinical decision pathway.
The change likely reflects a growing trend of
acceptance for SNB as a standard staging method
for OSCC, in light of the promising preliminary 3-
year results from the multi-institutional Sentinel
European Node Trial published in 2015.34
Although beyond the scope of this volume, a
detailed discussion on the technical aspects and
specific applications of SNB within OSCC37 can
be found elsewhere.
National Comprehensive Cancer Network
Recommendations for the N1 Neck
The management of gross clinically detected or
radiographically detected regional disease is far
clearer than determining the optimal manage-
ment of the N0 neck with an early-stage
primary. In OSCC, because the at-risk nodal ba-
sins potentially harboring metastatic disease
include levels I to III of the neck,38 the NCCN
Guidelines recommend accordingly in selective
neck dissection of these levels for cN0 OSCC.
Although the decision to perform elective select
neck dissection for cT1-T2 N0 stages is based
on the assessment of SNB or DOI of the primary
tumor, the 2018 NCCN Guidelines recommend
END for cT3-T4 N0 OSCC regardless of DOI or
status of SNB, considering the high risk of occult
nodal metastasis with more-advanced T stage.
Similarly, the NCCN Guidelines recommend ther-
apeutic neck dissection for any N1 disease,
regardless of clinical T stage.16 The NCCN
Guidelines recommend, however, determining
the extent of neck dissection, either selective or
comprehensive, on the basis of the preoperative
clinical staging and the judgment of the sur-
geon.16 The 2018 NCCN Guidelines offer the
following recommendations on the extent of
neck dissection for the following clinical N-stage
categories:
 cN1, cN2a, cN2b, cN2c—selective neck
dissection or comprehensive neck dissection
at providers discretion
 cN3—comprehensive neck dissection
Which levels of the neck to include in selective
therapeutic neck dissection are determined by
the anatomic subsite of the primary tumor as well
as the location of gross nodal involvement on pre-
operative clinical and radiologic evaluation. Selec-
tive neck dissection for treatment of patients with
clinically node-positive disease, however, risks
the possibility of occult metastases remaining un-
treated in levels beyond the boundaries of selec-
tive dissection in patients with more-advanced
N stages at the time of diagnosis. Therefore,
comprehensive neck dissection for clinically
node-positive disease removes the entire regional
nodal basins at risk with greater chances of
completely removing metastatic disease. Although
the primary purpose of therapeutic neck dissec-
tion is to remove metastatic nodal disease from
the neck, an additional critical role is in pathologic
staging to determine the role of adjuvant therapy.
The indications for adjuvant therapy based on
the NCCN Guidelines for OSCC can be found in
Table 3.
SUBSITE-SPECIFIC CONSIDERATIONS FOR
MANAGEMENT OF ORAL CAVITY
SQUAMOUS CELL CARCINOMA
As with all prior updates to the AJCC staging and
NCCN Guidelines, a period of recalibration inevi-
tably follows during which oncologic providers
integrate their current clinical practice patterns
and personal treatment philosophies or risk con-
flict with the new and contemporary treatment al-
gorithms. After any significant update to the
standards of practice pathways, providers must
often relinquish long-held beliefs regarding tumor
management principles that are at odds with the
most current evidence supporting newly recom-
mended treatment protocols. Accordingly, the
following sections of this article summarize the
management of OSCC based on historical and
contemporary strategies specific to anatomic sub-
sites within the oral cavity.
The Tongue
The oral tongue, or anterior two-thirds, is the most
common subsite of origin for squamous cell carci-
noma in the oral cavity.39 The tongue is considered
a high-risk subsite for OSCC owing to the

propensity for regional nodal metastasis through a
rich lymphatic network and to a low resistance to
tumor ingress and metastasis by an ill-equipped
muscular composition.40 As previously stated,
the primary, definitive management of OSCC of
the tongue with curative intent is surgery alone or
with adjuvant radiation or chemo-RT, as indicated
by pathologic staging. Reconstructive options af-
ter tongue resection are largely dependent on the
size of the defect after ablation, the overall func-
tional status of the patient, the anticipated need
for adjuvant treatment modalities, and the hopes
of preserving functions of the tongue, including
speech, mastication, and deglutition. From a
reconstructive standpoint, small defects of the
tongue can be easily managed with primary
closure; moderate-sized defects with skin grafts
or biologic dressings; and large partial glossecto-
mies, hemiglossectomies, and subtotal or total
glossectomies are most ideally managed by
locoregional flaps (ie, facial artery myomucosal
flap and submental island flap) or free tissue trans-
fers (ie, radial forearm free flap, anterolateral thigh
flap, lateral arm flap, medial sural artery perforator
flaps, and profunda artery perforator flap).
The management of early-stage T1-T2 OSCC of
the tongue with a cN0 neck has remained a contro-
versial topic within the field of oncologic surgery.
Given the propensity of occult metastasis for
OSCC of the tongue at presentation,40
many surgeons recommend END even for early
T-staged cancers with the benefit of prognostic in-
formation from identifying pathologic regional
nodal disease at the time of surgery. In the past,
primary tumor subsite and clinical T staging were
the most important factors in determining the risk
of occult nodal metastasis to guide the decision
for END. Despite some variability in the recommen-
dations of surgeons for END in early T-staged cN0
tongue cancers, evidence suggests that a large
portion recommend END for patients with primary
tumors of cT2 tongue stage or greater.41 Such
practice patterns are now considered in the light
of updates to the AJCC Cancer Staging Manual
and the NCCN Guidelines, which recommend
management based on objective thresholds of
DOI at the primary site to estimate the risk for
occult nodal metastasis. The eighth edition of the
AJCC Cancer Staging Manual incorporates 5-mm
increments of DOI into a revised T stage for patho-
logic upstaging based on increasing levels of DOI.
The eighth edition AJCC T staging for OSCC, how-
ever, is conspicuously devoid of any specific risk
stratification based on the anatomic subsite of
origin of the primary tumor within the oral cavity.
Similarly, although the NCCN currently recom-
mends a DOI threshold of 4 mm as the inflection
Oral Cavity Cancer 9
point in which to consider END for OSCC, this
recommendation is not made with regard to any
anatomic subsite-specific risk and is instead
generalized to all oral cavity primaries as a whole.
The results of recent investigation suggests that
for high-risk anatomic subsites within the oral cav-
ity an even lower threshold of DOI (2 mm for tongue
and 2–3 mm for FOM) should be used for recom-
mending END.7 Most surgeons, however, ascribe
to a 4-mm threshold for DOI to recommend END
in cases of early-stage cN0 tongue carcinomas
due to the significant risk of occult nodal metas-
tasis at the time of diagnosis. SNB remains a viable
alternative in the staging of early T-staged cN0
tongue cancers when preoperative DOI assess-
ments are not available or remain equivocal after
initial diagnostic biopsy. Primary tongue tumors
that extend to the FOM, however, are poorly suited
for the use of the technique of SNB.
The Floor of Mouth
After the oral tongue, the FOM represents the sec-
ond most common site of origin for OSCC. FOM
carcinomas present with unique treatment chal-
lenges owing to the proximity to other important
structures of the oral cavity, to the limitations in sur-
gical access, to a propensity for positive surgical
margins, and to the risk of bilateral cervical metas-
tases.22,42 Resection of FOM carcinomas often ne-
cessitates the composite of adjacent anatomic
structures, such as the tongue, mandible, alveolar
ridge, sublingual gland, and tonsillar pillars, to
obtain an adequate oncologic margin around the
primary tumor. Therefore, reconstructive options
for FOM carcinomas remain dependent on whether
removal of the tumor requires soft tissue excision
or more complex composite tissue resection
including bone. Small superficial OSCCs involving
the FOM are treated with local excision and pri-
mary closure, whereas larger local resections
may require reconstruction with split-thickness
skin grafting or locoregional tissue flaps to prevent
cicatricial scarring and postoperative tethering of
the tongue. Large FOM carcinomas requiring
radical resection are best managed with free tissue
transfer given the often complex and composite
nature of the defect. Occasionally multiple free
flaps, chimeric free flaps, or combined regional
flaps with free tissue transfer are required for
optimal postoperative outcomes (Fig. 3).
The FOM is considered a high-risk anatomic
subsite for occult nodal metastases and the
extent of locoregional management parallels
that of carcinomas involving the oral tongue.
The FOM is carries a high risk of bilateral
cervical lymph node metastasis, even in cases
10 Ettinger et al

Fig. 3. A complex ablative defect resulting from advanced-staged FOM squamous cell carcinoma. (A) Clinical
photograph of primary tumor. (B) Planned chimeric osteomusculocutaneous fibular free-flap with 2 separate
skin paddles. (C) Elevated chimeric fibula flap, including with soleus muscle and skin paddle components. (D)
Composite ablative defect. (E) Inset of chimeric fibular free flap.

of early-stage unilateral primary tumors.22 The
risk of contralateral or bilateral cervical metasta-
ses has been shown 50% greater for FOM pri-
maries compared with ipsilateral tumors of the
tongue, which also pose risk for contralateral
lymph node metastasis.22 Accordingly, many sur-
geons perform bilateral END for cN0 disease
involving both FOM and midline oral tongue pri-
mary tumors.19
The application of the SNB technique in
detecting occult nodal metastasis for FOM carci-
nomas remains open to debate.27,35,36 Due to the
anatomic proximity of the FOM to the first-
echelon lymph nodes in level I of the neck, radio-
tracer shine-through can obscure signals from
sentinel nodes and impair their intraoperative
identification. Although some investigations
have shown successful application of SNB for
FOM primaries,33,34 the NCCN Guidelines
currently recommend caution in employing the
technique for FOM carcinomas.16
The Retromolar Trigone
The retromolar trigone (RMT) is a relatively uncom-
mon site of origin for OSCC relative to other oral
cavity subsites. Therefore, high-quality evidence
supporting optimal treatment protocols for OSCC
of the RMT have been lacking. Although the result
has been some variability in treatment strategies,
surgery is heavily favored as the definitive modality
for curative treatment of cancers of the RMT.
Although previously categorized as intermediate
risk for regional metastases, more recent retro-
spective cohort studies have demonstrated
rates of occult nodal metastases for cN0 RMT

carcinoma ranging from 8.3% to 63.6%.43
Accordingly, the use of new guidelines introducing
DOI of the primary tumor and the acceptance for
the staging of OSCC with SNB may better stan-
dardize the regional management of OSSC arising
from the RMT. Nonetheless, an ongoing debate on
the management of OSSC of the RMT stems from
the extent of bone resection required to provide
adequate resection of the primary tumor. The
oncologic soundness of performing marginal man-
dibulectomy versus segmental mandibulectomy
remains uncertain and unresolved by the currently
available literature on the topic.43–45 The clinical
decision regarding the extent of bone resection
required for carcinoma of the RMT demands care-
ful scrutiny of preoperative imaging to assess for
signs of mandibular bone invasion. The proximity
of the RMT to multiple other anatomic subsites
of the oral cavity and oropharynx makes surgery
in this area particularly challenging for large
advanced-stage tumors. Depending on the direc-
tion and extent of primary tumor spread, RMT
carcinomas can involve the masticator space,
tonsillar pillars, soft palate, tonsillar fossa, para-
pharyngeal space, tongue base, FOM, buccal mu-
cosa, posterior maxilla, and palate. Accordingly,
the reconstructive options for carcinoma of the
RMT are predicated on the extent of involved
anatomic subsites and include primary closure,
skin grafting, locoregional tissue flaps, or compos-
ite free tissue transfer based on the extent of the
defect.
The Mandibular Alveolar Ridge and Gingiva
Although occasionally grouped together in the
classification of oral cavity subsites, maxillary
and mandibular alveolar ridge OSCC are sepa-
rate clinical entities with different oncologic and
reconstructive treatment considerations. The
mandibular alveolar ridge and gingiva is an un-
common site for oral cavity carcinomas, consti-
tuting only 6.4% of OSCC.46 Alveolar OSCC
can frequently resemble infectious, traumatic, or
inflammatory conditions of the gingiva, which
can delay diagnosis, especially after evaluation
by inexperienced clinicians. Misdiagnosis as
infection or inflammation often leads to inappro-
priate surgical procedures, such as tooth
extraction, or incision and drainage that can
compromise oncologic outcomes. Multiple
studies have demonstrated increased risks of
medullary bone invasion and regional nodal
involvement with reduced 5-year survival rates
for alveolar OSCC for patients undergoing dental
extraction prior to definitive oncologic treat-
ment.47–51 The mechanism proposed for the
Oral Cavity Cancer 11
phenomenon is the breach of the barrier function
of the tooth and permits direct invasion of tumor
into the medullary bone through the open extrac-
tion site.
Carefully evaluating osteolysis surrounding a
primary tumor on preoperative imaging is critical
in distinguishing cortical bone erosion from frank
medullary bone invasion. Intramedullary bone in-
vasion is a critical clinicopathologic factor that
upstages oral cavity tumors to the T4a stage
independent of size of the primary tumor. Trans-
cortical bone invasion implies aggressive dis-
ease, with segmental mandibular resection
indicated for cases with a high clinical suspicion
of medullary bone involvement. With marginal
mandibulectomy, intraoperative fresh frozen
section of the medullary cavity can assess the
tumor resection margin for involvement by tumor
when findings on preoperative imaging and clin-
ical examination are equivocal.52
Accurate identification of bone invasion is crit-
ical for planning reconstruction. Gross bone inva-
sion stages the primary tumor to T4, for which
adjuvant therapy is indicated (see Table 3). With
the anticipation of adjuvant RT, reconstruction
with vascularized free tissue transfer is strongly
preferred for restoring mandibular continuity and
minimizing the risk for post-treatment sequelae
associated with nonvascularized reconstructions
that are subjected to RT.
The Maxillary Alveolar Ridge, Gingiva, and
Hard Palate
The maxillary alveolar ridge and hard palate are
the least common sites of origin for OSCC53
and considered together as a single anatomic
subsite because of their contiguous anatomic
relationship and the similar clinicopathologic
behavior of tumors arising from these subsites.54
Tumors of the maxillary alveolus and hard palate
have been categorized as low-risk sites for occult
nodal metastasis and END has often been de-
ferred for cN0 disease regardless of primary
tumor size or depth. Recent investigations, how-
ever, have found higher than expected rates of
occult nodal metastasis ranging from 20% to
36.1% for advanced-stage maxillary alveolar
and palatal OSCC, calling into question the valid-
ity of deferring END.21,53,55,56 Although some in-
vestigators have suggested END for OSCC of
the maxillary ridge and palate staged T2 or
greater,53 the breadth of available literature sup-
ports END only for patients with T3 and T4 pri-
mary tumors.21,55,56 Clarity is lacking on the role
of T-stage alone in the decision for END or the
consideration for DOI at the primary site in the
12 Ettinger et al
maxillary ridge or palate. A threshold for DOI of 3
mm to 4 mm specific for tumors of the maxilla
alveolar ridge and palate has been suggested
by one of the few investigations evaluating the
impact of DOI within subsites of the oral cavity
on predicting occult nodal metastasis.7 The find-
ings are consistent with the recommendations of
the NCCN Guidelines of END for oral cavity carci-
nomas with DOI of the primary tumor greater than
4 mm, irrespective of subsite.
The reconstructive consideration unique to
OSSC of the maxillary alveolar ridge and palate
is the complex 3-D structure of defects at this
subsite. Composite tissue resections of the
maxilla result in defects that require careful
consideration of factors in planning for recon-
struction: to separate oronasal and oroantral
communication, to restore the loss of dentoal-
veolar segments, to preserve normal phonation,
and to provide adequate facial soft tissue sup-
port. Although rehabilitation of function with a
prosthodontic obturator for defects of the maxilla
remains a viable option, reconstruction with
locoregional flaps and free tissue transfer may
provide patients with functional and cosmetic
outcomes equaling or exceeding that of alloplas-
tic reconstructions.57 Free tissue transfer com-
bined with conventional or zygomatic implants
facilitates options in the rehabilitation of patients
with defects of the maxillary ridge and palate.
The reconstructive plan should be tailored to
the needs and desires of individual patients
in relation to their premorbid functional status
and anticipated functional status after surgery
(Fig. 4). Multidisciplinary treatment planning with
a maxillofacial prosthodontis remains an invalu-
able resource in optimally restoring complex
composite defects involving the maxillary alve-
olus and hard palate.
The Buccal Mucosa
The buccal mucosa is a site of origin from which
OSCC rarely arises in patients of North America
and Western Europe, accounting for only 10%
of primary tumors of the oral cavity.58,59 In re-
gions of China, South East Asia, and India, how-
ever, carcinoma of the buccal mucosa is one of
the most common forms of OSCC.58–62 This
geographic variation in the incidence of OSCC
of the buccal mucosa results from the endemic
regional practice of chewing betel quid, or pan,
a potent carcinogen of the buccal mucosal sub-
site.58,60 OSCC of the buccal mucosa was
considered a less-aggressive tumor with a
lower risk of cervical metastasis and locoregional
recurrence. Recent investigations, however, have
challenged the notion of low-grade behavior for
OSCC of the buccal mucosa with evidence to
the contrary.58–62 Cohort series have identified
high rates of locoregional recurrence for cancers
of the buccal mucosa, attributing a unique lack of
anatomic barriers to spread once a tumor in-
vades beyond the fascia of the buccinator mus-
cle and into the buccal fat pad.58–62 Rates of
occult nodal metastasis for OSCC of the buccal
mucosa in Western populations range from
13% to 32%,59,61,62 with similar rates in Asian co-
horts (28.4%).59,61–63 With the risk of locoregional
recurrence and occult nodal metastasis compa-
rable to other subsites of the oral cavity consid-
ered at high risk, END is recommended for
OSCC of the buccal mucosa staged T2 or greater
or found with DOI exceeding 3 mm to 4 mm.61
That recommendation is consistent with the cur-
rent NCCN Guidelines and updated AJCC Can-
cer Staging Manual for elective dissection of the
neck in patients with cN0 necks and primary tu-
mors of the oral cavity.
From an ablative standpoint, small early-stage
buccal mucosal tumors are often amenable
to simple local resection, whereas larger
advanced-stage tumors require complex com-
posite resection, perhaps involving facial skin,
mandibular or maxillary ridge, or the oropharynx,
depending on the extent of tumor extension. Pri-
mary closure or local tissue flaps, such as the
buccal fat pad advancement flap, are suitable
for reconstruction of small defects of the buccal
mucosa. Composite or full-thickness defects
necessitate regional or free tissue transfer for
adequate functional and cosmetic outcomes.
Submental island flaps or supraclavicular flaps
can provide regional tissue well suited to replace
the thin pliable buccal mucosal and skin of the
cheek. The first-echelon lymph nodes draining
the buccal mucosa are in levels Ia and Ib of the
neck. Gross or suspected lymphadenopathy in
level I precludes reconstruction with a submental
island flap that might compromise oncologic
principle.64 Full-thickness defects of the buccal
mucosa and cheek from ablation of large,
advanced-stage tumors may require folded skin
flaps for both intraoral and external facial lining.
Multiple free flaps may be required to address
more complex composite defects in which multi-
ple adjacent anatomic subsites are contiguously
involved by direct tumor extension (Fig. 5).
Free-flaps well suited to folding for reconstruction
of the buccal mucosa and cheek skin include the
radial forearm free flap, the anterolateral thigh
flap of nonobese patients, the thoracodorsal ar-
tery perforator flap, the lateral arm flap, and the
profunda artery perforator flap.
 Oral Cavity Cancer 13

Fig. 4. Examples of maxillary reconstructions using of local flaps and grafts, free-tissue transfer, and combined
zygomatic implant constructs. (A–C) Combined buccal fat pad and mucosal advancement flap for closure of a par-
tial maxillectomy defect. (D–F) Split-thickness skin grafting for reconstruction of a maxillectomy defect limited to
the alveolus. (G–I) Pedicled palatal rotational flap for oroantral separation following partial maxillectomy. (J–M)
Composite total maxillectomy defect reconstructed with radial forearm free flap, bilateral zygomatic implants,
and implant supported hybrid prosthesis.
14 Ettinger et al

Fig. 5. Advanced-stage buccal mucosa squamous cell carcinoma with concomitant lip, mandible, and external
facial skin involvement. (A) Primary tumor prior to resection. (B) Composite resection of primary tumor with ipsi-
lateral select neck dissection. (C) Elevated anterolateral thigh flap for buccal mucosal and cheek reconstruction.
(D) Elevated osteocutaneous fibular free flap for mandibular reconstruction. (E) Fibular free flap inset with micro-
vascular anastomosis completed. (F) Anterolateral thigh flap inset in folded configuration for buccal mucosal and
external facial skin relining.

SUMMARY treatment pathways and adapt their clinical prac-

The primary definitive management strategy of
OSCC is surgery followed by adjuvant RT or
combined radiation and chemotherapy based
on regional nodal status, high-risk pathologic
features, or advanced-stage disease. Recent
changes to AJCC staging and NCCN manage-
ment guidelines now incorporate new pathologic
parameters, such as DOI and ENE, to improve
hazard discrimination in outcome prognostication
and guide clinical decision making. Maxillofacial
surgeons must continually remain apprised of
the most current staging algorithms and
tice patterns to reflect most contemporary stan-
dards of care relative to oncologic management
of OSCC.
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