Download Controversies in the management of retromolar trigone carcinoma

CLINICAL REVIEW
David W. Eisele, MD, Section Editor
CONTROVERSIES IN THE MANAGEMENT OF
RETROMOLAR TRIGONE CARCINOMA
Tareck Ayad, MD,1 Louis Guertin, MD,1 Denis Soulières, MD,2 Manon Belair, MD,3
Stéphane Temam, MD,4 Phuc Felix Nguyen-Tân, MD5
1
Department of Otolaryngology–Head and Neck Surgery, Hôpital Notre-Dame, Centre Hospitalier
Universitaire de Montréal, Montreal, Quebec, Canada. E-mail: [email protected]
2
Department of Hematology-Oncology, Hôpital Notre-Dame, Centre Hospitalier Universitaire de Montréal,
Montreal, Quebec, Canada
3
Department of Radiology, Hôpital Notre-Dame, Centre Hospitalier Universitaire de Montréal,
Montreal, Quebec, Canada
4
Department of Otolaryngology–Head and Neck Surgery, Institut Gustave Roussy, Villejuif, France
5
Department of Radiation Oncology, Hôpital Notre-Dame, Centre Hospitalier Universitaire de Montréal,
Montreal, Quebec, Canada
Accepted 14 July 2008
Published online 20 November 2008 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/hed.20956
Abstract: Our objective is to discuss the current controversies
that surround the management of retromolar trigone (RMT) cancer. We conducted this literature review to discuss trigone cancer. RTM and anterior pillar cancers should be studied separately. Preoperative clinical and radiographic assessments need
to be further investigated to establish their reliability at predicting
bone invasion. In the absence of suspicion of bone invasion, surgery and radiotherapy seem to give similar results, but recent
reports indicate a greater benefit if they are used in combination.
Some authors have advocated systematic segmental resection
for all RMT cancers but marginal mandibulectomy is a reasonable option in selected cases. Standard treatment for RMT cancers with N0 necks is selective neck dissection or radiation
therapy, depending on the modality of treatment of the primary. Allowing a better understanding of the evolution of RMT
cancer and its response to different treatment modalities
requires efforts to report different institutional experience with
Correspondence to: T. Ayad
Contract grant sponsor: Bourse André Lanthier, from Centre Hospitalier
Universitaire de Montréal.
C
V
2008 Wiley Periodicals, Inc.
398
Retromolar Trigone Carcinoma Controversies
this rare tumor.
398–405, 2009
C 2008 Wiley Periodicals, Inc. Head Neck 31:
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Keywords: retromolar trigone; cancer; oral cavity; surgery;
radiotherapy
Retromolar trigone (RMT) carcinoma is a relatively rare tumor. Little information has been
published concerning their treatment, and questions remain concerning the best management.
Available options encompass surgery, radiation
therapy, or a combined therapy. In 1959, Barbosa
published the first series of patients with RMT
carcinoma treated by surgery or radiotherapy
(RT).1 Since then, there is still controversy on the
best treatment for RMT cancer.2–4
It is well accepted that bone invasion suspicion
makes surgery mandatory if a curative treatment
is considered. For lower stages, the optimal treatment is still debated. Some cancer institutes favor
HEAD & NECK—DOI 10.1002/hed
March 2009
surgical treatment; others prefer radiation therapy as primary treatment preserving surgery for
locoregional failures. More recently a trend for
systematic combination therapy (surgery and
radiation therapy) has been seen in some institutions. To date, no randomized controlled study has
been published on RMT cancers. Only retrospective studies can be found in the English-language
literature. Our objective is to discuss the current
controversies in the management of RMT carcinomas according to the literature. The authors have
chosen to limit the analysis and discussion to
these specific matters of controversies.
PRIMARY SITE LOCALIZATION
The RMT is in continuity with the anterior pillar
in its medial part, the upper gum superiorly, the
lower gum inferiorly, and the buccal mucosa laterally. While the RMT is a subsite of the oral cavity,
the anterior pillar is a subsite of the oropharynx.
Even though they pertain to different anatomic
sites, 3 studies group the RMT and anterior pillar
cancer together.5–7 Lo et al found no statistically
significant difference between RMT and anterior
pillar cancers in terms of primary control in a
study with 137 patients treated by radiation
therapy.6 The differences between these 2 subsites
for regional control and survival were not
mentioned.
The grouping of anterior pillar and RMT cancers can be supported by their geographic proximity that makes identification of the exact primary
site often difficult. Confinement of a cancer to the
RMT occurs only in 15.5% to 26.3% of the cases.
The tumor spreads to the anterior pillar in 80% to
84.5% of the cases and the majority of them
invade 3 or more subsites of the oral cavity and
oropharynx.8–10 Despite this tendency to spread
to the anterior pillar, the majority of the authors
study these subsites separately. In fact, RMT cancer is more prone to bone invasion because of its
close proximity to the mandible and the maxilla.
Moreover, it is considered to have a different
growth pattern than anterior pillar cancer. RMT
cancers tend to spread upward along the pterygomandibular raphe and deep in the masticator
space after an initial superficial growth phase.11
In the published studies, the authors rely on the
written and/or drawn description of the tumor to
classify it as a RMT cancer instead of an anterior
pillar cancer. Because of the retrospective nature
of these studies and the difficulty to assess the
exact initial subsite of a large tumor, misclassifi-
Retromolar Trigone Carcinoma Controversies
Table 1. Local control rates (%) according to T classification
for retromolar trigone cancers and lateralized lesions
of the oral cavity.
T1
6
Lo et al
Byers et al9
Mendenhall et al15
Ayad et al8
Barker et al7
Richaud et al14
71
92
75
85
82.6
T2
70
88
65
90
81
67.7
T3
76
90
65
85
81.8
T4
60
75
61
75
64
50
cation of anterior pillar cancers as RMT cancers is
a concern.
As previously mentioned, RMT cancers are
considered prone to mandible invasion. Reported
rates of pathologically proven bone invasion
have been inconsistent, ranging from 12% to
53%.5,9,11,12 In the study by Kowalsky et al, 114
consecutive patients underwent a segmental
mandibulectomy as part of their treatment.13
Mandibular invasion was seen in 14% of the cases
and maxillary invasion in only 3 cases. Hao et al
found a higher rate of bone invasion both in the
maxilla (22%) than in the mandible (18%) in a series of 50 patients.11
PRIMARY SITE STAGING
The absence of correlation between T staging and
local control is a frequent finding in the literature
with RMT carcinomas and other lateralized
lesions of the oral cavity.14 Only T4 lesions are
clearly associated to a worse local control, with
bone invasion and masticator space extension established as unfavorable prognostic
factors.6–9,14,15 Involvement of adjacent structures such as the masticator space, as opposed
to T classification, is more relevant.11 For lower
stages, local control does not appear to be influenced by the tumor size (Table 1). This could be
explained by the superficial growth of RMT carcinomas. Cancer growth in this area is limited
in deeper planes by the periosteum and bone.
As a consequence, for each T classification, cancers arising and spreading in this area contain
proportionately fewer cells than cancers that
grow spherically, such as tongue or tonsillar
fossa tumors. As stated by Barker et al ‘‘the
stage according to diameter of the lesion (. . .) is
not a reflection of the volume of the cancer.’’7
Tumors of the RMT are associated with areas
of leukoplakia and erythroplakia in adjacent mucosa. Histopathologically, it has been documented
HEAD & NECK—DOI 10.1002/hed
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399
that in oral erythroplakia of the homogenous type,
51% showed invasive carcinoma and 40% carcinoma in situ.16 If underestimated, these lesions
could be excluded of the radiation or resection
field. Another potential contributing factor to the
discrepancies observed in local control and T classification is the erroneous staging of the disease.
Small lesions can involve minimal foci of osseous
invasion that may be missed by physical examination or imaging. Stage underestimation can result
in inappropriate treatment and thus, in erroneous
local control rates for a particular stage.
PREOPERATIVE ASSESSMENT
Bone invasion has a strong impact on the management of RMT cancer. To maximize the cure rate, a
marginal or segmental mandibulectomy is
required when periosteal or bone invasion is suspected. It is unwise to rely solely on clinical examination to assess bone integrity in oral cavity cancers. In the study by Weisberger and Kimmelman,
33% of patients with histologically proven tumoral bone infiltration showed no clinical sign of
bone invasion.17 Tsue et al found that 34% (11 of
32) of patients with clinically free mobile tumors
had histologic bone tumoral infiltration and only
44% (14 of 32) of patients with clinical tumor fixation had confirmed histologic bone infiltration.18
However, Jones et al found that clinical assessment is an accurate method of predicting bone
invasion with a sensitivity of 91% and negative
predictive value (NPV) of 93%. These contradictory results make radiological assessment a useful
adjunct to evaluate the need for mandible resection.19
Plain radiography, panorex, orthopantomography, MRI, and CT have all been used to assess
mandibular integrity, with the latter 2 being the
most commonly used nowadays. The use of CT in
the assessment of mandibular invasion in oral
cavity cancers is controversial. False-negative
rates varying from 0% to 35% have been
reported.20–25 In a series of 26 patients, Lane et al
evaluated the parameters of accuracy for bone
invasion assessment by a CT with 5-mm-thick
axial sections. They found the following results:
sensitivity 50%, specificity 91%, NPV 61%, positive predictive value (PPV) 87.5%.12 According to
these results, CT is reliable when bone invasion is
detected (PPV, 87.5%.) but a negative scan is of no
use because half the patients with histologic bone
invasion show no radiologic sign of bone invasion
(NPV, 61%; sensitivity, 50%). As stated by the
400
Retromolar Trigone Carcinoma Controversies
authors, these suboptimal results could be
explained by the thick section studies (5 mm) and
the lack of high-resolution bone algorithm. Accuracy of CT imaging in assessing bone invasion for
RMT cancer is still to be established.
MRI is a valuable tool in assessing surrounding structures including mandible as shown by
Crecco et al. In this retrospective study, the
results of MRI findings and pathological data
were compared for 22 patients with RMT cancers.26 MRI appeared to be highly accurate to
study the T classification and the relationships
with the surrounding structures. In assessing
bone marrow invasion the sensitivity was 100%
but the specificity was 77%. As for CT, further
evaluation of MRI accuracy to detect mandibular
invasion in RMT cancers is needed.
UNIMODAL TREATMENT OR COMBINED THERAPY
To date, no clear recommendations have been proposed for the treatment of RMT cancers. Because
of the rarity of this tumor at this subsite, retrospective studies reported limited number of
patients, and a prospective randomized study is
not feasible. We have to rely on retrospective studies with their inherent fallbacks and limitations.
Out of 14 studies published on RMT cancer treatment in the English-language literature between
1959 and 2007, only 6 of them compared 2 or more
treatment modalities.1,9,10,15,27,28 In the other
studies, patients receive 1 treatment modality
(surgery or radiation therapy) and the results are
compared to historical series. However, patient
and tumor characteristics are not comparable
between these studies, and the reported outcomes
are not uniform. For example, cause-specific
survival is not mentioned in 5 of these
studies.5,7,9,13,29
The results and conclusions of the 4 most
recent comparative studies are summarized in
Table 2. We did not include the 2 studies by Barbosa (1959 and 1962) in this table because of the
short follow-up period and the evolution of radiation therapy techniques since then.1,28 In 1984,
Byers et al reported their experience with 110
patients with RMT cancers treated with surgery
(n 5 46), RT (n 5 50) or combined treatment (n 5
14) with minimal 2 years of follow-up.9 Median follow-up is not mentioned. In this study, the local
and regional controls were similar between these
groups of patients, and Byers concluded that single-mode therapy is equivalent to a combined
therapy. Of note, the surgery groups included
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Table 2. Studies comparing different treatment modalities for retromolar trigone carcinomas.
Authors/year of publication
Byers et al,9 1984
Huang et al,10 2001*
Mendenhall et al,15 2005*
Binahmed et al,27 2007
Local
control, %
Regional
control, %
Locoregional
control, %
CSS,
%
OS,
%
89.5
84
–
–
–
90
–
–
90
26
10
87.5–92
84
–
39
–
–
77
63
–
15
64
–
71
–
–
56
71
31
69
–
56
35
15
48
–
–
–
48
–
52
–
40
57
29
20
–
–
–
–
–
–
–
–
45
64
Treatment
Patients
Surgery
RT
Combined treatment
(preoperative RT)
Combined treatment
(postoperative RT)
Radiotherapy alone
Combined treatment
(pre or postoperative RT)
RT
Combined treatment
(postoperative RT)
RT
Surgery
110
–
Abbreviations: CSS, cause-specific survival; OS, overall survival; RT, radiotherapy.
*Studies with statistically significant differences between treatment modalities (p < .05).
more T3-T4 cancers and cause-specific survival
according to treatment modality is not reported in
this study.
Binhamed et al reported their experience with
RMT cancer treatment in the province of Manitoba, Canada.27 Among 76 patients with RMT cancer, 12 were treated with palliative intent. Surgery was used as the primary treatment modality
in 20 patients. Radiotherapy was used as the primary treatment modality in 29 patients with 3
patients having a neck dissection for persistent
disease. Fifteen patients received postoperative
radiotherapy. Median or minimum follow-up is
not mentioned. The 5-year overall survival rates
for patients treated with surgery was 64%, with
surgery and radiotherapy 57%, and 45% when
radiotherapy was elected as a single treatment
modality. The difference between these 3 groups
was not statistically significant (p 5 .0270).
Locoregional control and cause-specific survival
according to initial treatment modality have not
been studied.
Two recent comparative studies favor combined treatment with surgery and RT over RT
alone.10,15 Mendenhall et al compared RT alone to
RT combined with surgery in the treatment of
RMT cancer.15 The data on 99 patients treated
with curative intent between June 1966 and August 2003 were included in this study. The median
follow-up was 3.3 years and no patient was lost on
follow-up. Thirty-five patients were treated by definitive RT. Sixty-four patients had RT and surgery, preoperatively in 9 patients and postoperatively in 55 patients. In this study, multivariate
Retromolar Trigone Carcinoma Controversies
analysis showed that combined treatment significantly improved local control, local-regional control, distant metastasis-free survival, cause-specific survival, and overall survival. Huang et al
studied 65 patients in 3 treatment groups: definitive RT (n 5 15), preoperative RT (n 5 10), and
postoperative RT (n 5 39)10. The minimum followup was 5 years. Preoperative RT led to significantly better locoregional control and cause-specific survival (90% and 90%) than postoperative
RT (77% and 63%) and RT alone (56% and 31%).
These 2 studies share 1 drawback. Within the
same institution, similar groups of patients with
cancers of similar stage are treated differently
and the reasons to do so cannot reliably be established retrospectively.
RETROMOLAR TRIGONE SURGICAL MANAGEMENT
Clinical or radiological suspicion of bone invasion
indicates the need for segmental resection. Normal bone separated from the tumor by normal mucosa can usually be saved. Because RMT cancers
lie directly on the anterior ramus of the mandible,
bone resection must be systematically considered
even if there is no gross bone invasion. A question
remains as to whether a segmental or marginal
(partial-thickness) mandibular resection is
required for these patients. Bone involvement can
be assessed intraoperatively even if preoperative
clinical and radiological evaluations do not show
bone involvement. For an optimal evaluation, the
periosteum should be stripped from the mandible
cautiously. If medullary bone invasion or perineural spread is confirmed by intraoperative exami-
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401
nation, then segmental mandibulectomy is performed. If the bone is normal, periosteum histologic examination is performed. In the absence of
infiltrating disease, no resection or marginal
resection are reasonable options. In the presence
of neoplastic invasion, segmental or marginal
resections are both acceptable.
Irradiated mandibles do not present the same
dilemma. The pattern of invasion is different with
tumor extending directly through different points
in the cortex instead of the occlusal surface. In
these patients marginal mandibulectomy is usually contraindicated because extensive and diffuse
invasion of the mandibular body are expected.30
In 1959, Barbosa reported ‘‘the retromolar
operation,’’ an original procedure consisting of a
hemimandibulectomy with ‘‘en bloc’’ resection of
the pterygoid and masseter muscles and ipsilateral radical neck dissection.1 In 2 small series,
Barbosa concluded that surgery is superior to
radiation therapy.1,28 In the original study Barbosa compares 10 patients treated by surgery to
11 treated by radiation therapy.1 Even though his
results seem to favor surgery as the most
adequate treatment for RMT cancer, one must
restrain from adopting definitively the conclusions of this study. In fact, the variable and short
duration of follow-up (less than 2 years), the small
number of patients in each group, and the evolution of radiation therapy since 1959 limit the conclusions to be drawn from this study. Still, Barbosa has the merit to be the first to specifically
assess the effectiveness of different treatment
modalities for this small subsite of the oral cavity.
Kowalski et al applied ‘‘the retromolar operation’’ or an extended version of it to 114 patients
with RMT cancer in a 31-year period.13 Fortythree percent were classified as T1-T2. Radical
neck dissection was performed in 92.1% of the
patients. Sixty-six patients received postoperative
radiotherapy for positive margins or multiple
pathologic nodes. The median follow-up time was
25 months. Five-year disease-free survival and
overall survival were 48.9% and 55.3%, respectively. The rate of local recurrences (27.2%) encourage the author to suggest a more extensive
resection in appropriate patients and consider
radiotherapy in the patients with stages III/IV
cancer or when the tumor shows histologic criteria
of aggressiveness such as perineural spread and
vascular emboli.
Petruzzelli et al reviewed their experience
with posterior marginal mandibulectomy in the
management of SCC of the RMT and orophar-
402
Retromolar Trigone Carcinoma Controversies
ynx.31 Sixteen patients were included, with 13
treated for a primary located in the RMT. None of
the patients had clinical or radiographic evidence
of mandibular invasion. All patients received adjuvant radiation therapy and surgical treatment
of the neck. Two of the 16 marginal mandibulectomies demonstrated bone invasion. Median overall
survival was 37.5 months. Local control was
achieved in 15 of the 16 patients (93.75%). The
authors concluded that in the absence of clinical
or radiographic evidence of bone invasion, the posterior marginal mandibulectomy provides the necessary bony margin to prevent local recurrence.
Pascoal et al compared 20 patients who had a
marginal mandibulectomy to 22 who had segmental mandibulectomy for tonsillar or RMT (11
patients) cancer.29 The patients had locally
advanced disease without clinical or radiographic
evidence of bone invasion. Twenty-eight patients
(66.7%) were staged IVa (patients with lesions
that invaded deep/extrinsic muscles of the tongue,
the pterygoid muscle, or the hard palate) and 14
patients (33.3%) were staged IVb (patients with
invasion of the lateral pterygoid muscle, or pterygoid laminae, or the lateral wall of the nasopharynx). All patients underwent postoperative radiotherapy. The main treatment failure in both
groups was local and regional recurrence, at rates
of 35% in the marginal mandibulectomy group,
and 36.4% in segmental mandibulectomies. The
survival rate of the group treated by marginal
mandibulectomy was 55%.The survival rate of
the group treated by segmental mandibulectomy
was 45%. The authors believe that the unfavorable prognosis of advanced tumors without preoperative evidence of bone invasion should not encourage segmental resection, as preservation of
part of the mandibular arch does not appear to
worsen the survival rate and preserves function
and aesthetics.
In their review of the M. D. Anderson Cancer
Center experience with treatment of RMT cancers, Byers et al have used marginal mandibulectomy in 5 patients with no local failures and segmental mandibulectomy in 46 patients with 4
local recurrences (12.5%).9 No preoperative tumor staging for these patients has been provided.
In conclusion, marginal mandibulectomy
seems to be safe if there is the possibility of bone
involvement but no indicator of gross bone invasion. However, functional results and postoperative trismus according to the procedure have not
been reported. The indications of postoperative
radiotherapy are also unclear. Some institutes
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favor postoperative radiotherapy for limited bone
invasion with clear surgical margins, whereas
others do not.
ROLE OF CHEMOTHERAPY
Various phase III studies and recent meta-analysis have advocated concurrent chemotherapy and
RT for advanced stage III–IV head and neck carcinoma.32–34 Oral cavity lesions constituted only a
fraction of the population studied. According to
updated data from Notre-Dame hospital, 6
patients with stage III–IV carcinoma of the RMT
received concurrent platinum-based chemotherapy and RT from 1999 to 2006.8 Four of these
patients had a complete locoregional response.
One patient had persistent disease at the primary
and the neck and died of his disease. One patient
had a complete response at the primary and
underwent a neck dissection for a persistent neck
node and has been without disease since.
MANAGEMENT OF THE N0 NECK
Presence of pathologic neck nodes is a bad prognostic factor in RMT cancers. Histologically
involved lymph nodes are found in 26% to 80% of
the patients.5,9,11 Reports of controlateral neck
metastases are anecdotal.8–10 Thus, bilateral neck
dissection is recommended only if the lesion
crosses the midline anteriorly in the oral cavity or
posteriorly in the oropharynx. The modality of
treatment of the N1 neck should be the same as
the primary. The N0 neck is systematically
treated in the published reports. In the study by
Byers et al,9 114 consecutive patients underwent
surgical treatment of the RMT cancer with systematic neck dissection. N0 cases were treated at
least with a supra-omohyoid neck dissection. The
rate of occult metastases was 38% (16 of 42). In
the study by Antoniades et al, the rate of occult
metastases was 63.6% (7 of 11) but the number of
patients was limited and the study grouped together the anterior pillar and RMT cancers.5 In
the study by Hao et al, 50 patients with RMT squamous cell carcinomas were treated with curative
intent by surgery.11 The rate of occult metastases
was 8.3%. The rate of occult metastases varies
between studies but as long as their frequency is
not clearly established, systematic ipsilateral
neck treatment is recommended in N0 cases.
When surgery is the treatment selected, selective
neck dissection should be performed for N0 necks
with dissection of the level 2b if the lesion extends
Retromolar Trigone Carcinoma Controversies
to the oropharynx. Regional control has been similar in the series using surgery (89.5%)9,13 or radiotherapy (84%–90%)6,8,9 as primary treatment.
In recent years, sentinel node biopsy (SNB)
and SNB-guided elective neck dissection have
been used in selected centers to stage N0 necks for
T1-T2 cancers of the oral cavity. An increase in the
staging sensitivity is expected by localizing the
first-echelon nodes, including those with unpredictable drainage patterns, and then applying
advanced anatomo-pathologic study techniques to
a very reduced number of lymph nodes. In the
published studies, patients with cancer of all subsites of the oral cavity are grouped together, with
a few having RMT carcinoma. Nevertheless, reliability of the SNB for RMT cancers seems comparable to cancers arising in other subsites of the
oral cavity excluding the floor of mouth.35,36 It has
been found that SNB is less reliable for floor of
mouths cancers than for the other oral cavity subsites.35,36 The close proximity of the floor of mouth
to the nodal basin leads to difficulty in identifying
and harvesting the sentinel node, which is not the
case for RMT cancers. More studies are needed
before considering SNB or SNB-guided END as
part of a standard treatment for RMT carcinomas.
CONCLUSIONS
Literature on RMT cancer treatment demonstrates limitations on the establishment of guidelines due to the inherent characteristics of this tumor as well as the lack of uniformity between the
studies. For a better understanding of the evolution of RMT cancer and its response to different
treatment modalities, efforts should be made to
report different institutional experience with this
rare tumor. RTM and anterior pillar cancers
should be studied separately because cancers arising from the subsites require a different initial
assessment and seem to have different behavior
and prognosis. Preoperative clinical and radiographic assessments need to be further investigated to establish their reliability at predicting
bone invasion for RMT cancers.
In the absence of clinical or radiological suspicion of bone invasion, surgery and radiation therapy seem to give similar results, but recent
reports indicate a greater benefit if they are used
in combination. If there is suspicion of mandibular
or maxillary invasion, a primary surgical therapy
is the mainstay of treatment. Decision on whether
to treat a patient surgically or by radiation therapy based on clinical and radiographic grounds
HEAD & NECK—DOI 10.1002/hed
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403
appears to carry a significant amount of uncertainty. For this reason, many advocate systematic
surgical treatment with at least a marginal mandibulectomy for RMT cancers. Some authors have
advocated systematic segmental resection for all
RMT cancers but marginal mandibulectomy is a
reasonable option in selected cases. The experience of combined chemotherapy and RT for
advanced carcinoma of RMT is scarce, but is most
likely a reasonable option when there is no documented bone invasion and the patient is reluctant
to surgery. Surgery is then proposed as salvage
therapy.
Even if SNB has been used recently as a staging procedure for N0 necks in T1-T2 oral cavity
cancers, standard treatment for RMT cancers
with N0 necks remains selective neck dissection
or radiation therapy depending on the modality of
treatment of the primary.
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