Original Research
Otolaryngology–
Staged Surgery for Advanced Thyroid
Cancers: Safety and Oncologic Outcomes
of Neural Monitored Surgery
Behzad Salari, MD1, Rebecca J. Hammon, MD1,
Dipti Kamani, MD1, and Gregory W. Randolph, MD1,2
Sponsorships or competing interests that may be relevant to content are dis-
closed at the end of this article.
Abstract
Objective. Thyroidectomy with extensive multicompartment
bilateral neck dissections for advanced-stage thyroid cancer
may lead to increased risk of complications, including bilat-
eral recurrent laryngeal nerve (RLN) paralysis and hypopar-
athyroidism. A planned staged approach derived from a
detailed preoperative radiographic map is associated with a
low complication profile. This study evaluates oncologic
results and safety of neural monitored, staged thyroid
cancer surgery for management of advanced thyroid cancer.
Study Design. Case series with chart review.
Setting. Tertiary care center.
Subjects and Methods. With institutional review board
approval, 35 consecutive patients with advanced thyroid malig-
nancy and extensive nodal disease managed with staged sur-
gery between January 2004 and May 2013 by the senior
author (G.W.R.) were identified, and the oncologic and surgical
outcomes were reviewed.
Results. In total, 37.2% of patients had stage III or IV disease,
with extrathyroidal extension in 71.4%, vascular invasion in
51.4%, and RLN invasion in 17% of patients. A total of 34%
patients had positive lymph nodes in more than 5 nodal
compartments; the average positive lymph node yield was
17, and extranodal extension was present in 51%. Three
patients had RLN sacrifice, and there were no other cases
of temporary or permanent RLN paralysis; permanent hypo-
parathyroidism and chyle leak occurred in one patient each.
Locoregional recurrence occurred in 5.7% of patients after
a 147-week mean follow-up. In patients with papillary thyr-
oid carcinoma, median postoperative nonstimulated and sti-
mulated thyroglobulin levels were 0.2 and 0.75 ng/mL,
respectively.
Conclusion. A neural monitored, staged surgical approach
was conducted without significant adverse events in this
small sample and represents and effective alternative strat-
egy option to simultaneous bilateral surgery in the manage-
ment of thyroid cancer with extensive neck metastases.
Head and Neck Surgery
1–6
Ó American Academy of
Otolaryngology—Head and Neck
Surgery Foundation 2017
Reprints and permission:
sagepub.com/journalsPermissions.nav
DOI: 10.1177/0194599817697189
http://otojournal.org
Keywords
neck dissection, extensive thyroid cancer, bilateral surgery,
staged surgery, intraoperative nerve monitoring, recurrent
laryngeal nerve, complications
Received October 3, 2016; revised December 29, 2016; accepted
February 10, 2017.
T
herapeutic compartment-oriented nodal dissection is
recommended for macroscopic clinically apparent
nodal disease identified preoperatively in patients with
differentiated thyroid cancer and medullary thyroid cancer
(MTC).1 Increased extent of surgery, such as simultaneous bilat-
eral lymphadenectomy and total thyroidectomy, is known to
have increased rates of complications,2 and different approaches
have been described to limit the morbidity of surgery for
advanced thyroid cancer.3 Staged neck and thyroid surgery has
a long history: Dunhill in 1911, Pemburton in 1929, and Lahey
in 1936 performed staged thyroidectomy for severely toxic
cases of exophthalmic goiter in an effort to reduce perioperative
morbidity.4,5 During the past century, head and neck surgeons
have also staged neck dissections for aggressive squamous cell
cancer of the head and neck to reduce regional morbidity,
including bilateral jugular vein sacrifice and its consequences.6-
12
More recently, staged thyroid surgery has once again been
discussed as it relates to neural monitored thyroid surgery, spe-
cifically in the setting of loss of signal on the first operative
side, to reduce the risk of bilateral recurrent laryngeal nerve
(RLN) injury and airway compromise.13
The American Thyroid Association (ATA) 2015 guide-
lines now recommend that all patients with thyroid cancer
1
Division of Thyroid and Parathyroid Surgery, Department of
Otolaryngology, Massachusetts Eye and Ear Infirmary & Harvard Medical
School, Boston, Massachusetts, USA
2
Division of Surgical Oncology, Department of Surgery, Massachusetts
General Hospital, & Harvard Medical School Boston, Massachusetts, USA
Corresponding Author:
Gregory W. Randolph, MD, Department of Otolaryngology, Division of
Thyroid and Parathyroid Surgery, Massachusetts Eye and Ear Infirmary 243,
Charles St, Boston, MA 02114, USA.
Email: Gregory_Randolph@meei.harvard.edu
2 Otolaryngology–Head and Neck Surgery
should be preoperatively screened for nodal disease with
neck ultrasound and for bulky or widely distributed nodal
disease with a computed tomography (CT) scan.14 With this
careful radiographic preoperative approach, nodal disease
can be very accurately delineated preoperatively such that
patients with advanced disease with extensive, bulky, and
widely distributed nodal disease can be readily identified in
most circumstances, and staged approach can be considered
and discussed with eligible patients preoperatively.15
In the current study, patients with extensive bilateral cen-
tral and lateral neck nodes on preoperative imaging are
staged surgically with (1) the dominant lateral neck, ipsilat-
eral thyroid, and ipsilateral central neck along with the pretra-
cheal and prelaryngeal compartments performed first and (2)
the contralateral, less dominant lateral neck, thyroid, and cen-
tral neck completed after a recovery interval. If thyroid pri-
maries were bilateral, the largest dominant tumor side (which
also was typically the side of dominant largest nodal disease)
was done first. Here, we evaluate the safety and efficacy of
neural monitored, staged neck surgery as a treatment option
in patients presenting with extensive neck metastases.
Methods and Materials
A retrospective review of patients undergoing thyroid
cancer surgery with neck dissection from January 2004 to
May 2013 was conducted with institutional review board
approval (IRB Protocol 10-01-006: A Retrospective Study of
Staged Thyroid and Other Neck Surgeries). We identified 35
consecutive patients undergoing 70 thyroid and neck surgeries
with a staged approach for advanced thyroid cancer, performed
by a single surgeon (G.W.R.) in a tertiary surgical practice.
All patients underwent preoperative and postoperative laryngo-
scopy according to American Academy of Otolaryngology—
Head and Neck Surgery Foundation (AAO-HNSF) guide-
lines,16 and intraoperative nerve monitoring (IONM) was used
in all surgeries according to International Neural Monitoring
Study Group guidelines.17
The preoperative diagnosis and extent of locoregional and
distant metastases were recorded, including results of ultraso-
nography, CT scan, and other radiological reports; fine-needle
aspiration (FNA) cytology examination of primary thyroid
tumors and suspicious cervical lymph nodes in the central and
lateral compartments; and postoperative reports of final histo-
pathologic examinations. Thyroid cancer was staged using the
seventh edition of the American Joint Committee on Cancer
(AJCC) manual.18 Preoperative detection, extent, and mapping
of the nodal disease were accomplished by ultrasonography
and CT scan.19,20 Six surgically defined neck compartments
were used to describe nodal distribution: left lateral, left cen-
tral/paratracheal, midline central (ie, prelaryngeal and/or pre-
tracheal), right central/paratracheal, right lateral, and an
‘‘other/ectopic’’ nodal site (not contained in the central and lat-
eral typical compartments).20
Patient Selection
After detecting the extent and distribution of the nodal dis-
ease in patients with thyroid cancer preoperatively by using
imaging as noted above, we identified patients with advanced
thyroid cancers with bulky and widely distributed nodal dis-
ease. If we judged that a patient would require a surgery that
would be prolonged and morbid, if performed in one setting,
then we offered a staged approach. None of the eligible
patients rejected the staged approach. The staged approach
was a planned preoperative surgical strategy in all of these
patients; none of the staged surgeries in this series were
staged as an intraoperative decision based on the occurrence
of intraoperative complications.
Staging of Surgery
The compartments dissected in each stage of surgery are
described in the introduction section; we typically waited 8
to 10 weeks between the 2 surgeries.
Pre- and postoperative oncologic markers and post-
operative markers of hypoparathyroidism were reported,
specifically serum basal and stimulated thyroglobulin (ie,
thyroid-stimulating hormone [TSH]–suppressed or TSH-
stimulated) levels for patients with papillary thyroid car-
cinoma (PTC), calcitonin and carcinoembryonic antigen
(CEA) tumor marker for patients with MTC, and serum
calcium and albumin levels for all surgeries.
Operative notes, as well as office notes from otolaryn-
gology and endocrinology, were evaluated to establish type
of operation, surgical complications, locoregional recur-
rence, and survival. Patients with advanced PTC and MTC
who were treated with the staged approach were both
included due to the analogous nodal disease and manage-
ment issues.
Definitions of complications. RLN function was documented
by fiberoptic laryngoscopic examination preoperatively as
well as postoperatively. Temporary RLN paralysis was
defined as unintentional vocal cord paralysis (VCP) for less
than 6 months and permanent RLN paralysis was defined as
unintentional VCP persisting for greater than 6 months.
Postoperative hypoparathyroidism was separated into 2
groups: temporary and permanent. Temporary hypoparathyr-
oidism was defined as serum calcium of less than 8.4 mg/
dL requiring calcium and/or vitamin D supplementation
lasting less than 6 months; if it lasted greater than 6 months,
it was termed permanent hypoparathyroidism.
Data analysis. Collected data were inserted into an Excel
database (Microsoft, Redmond, Washington) and evaluated
by descriptive statistical analysis. The data for each variable
were expressed as frequency, percentage, and median or
mean 6 standard deviation.
Results
Thirty-five patients underwent staged neck surgeries, and a
total of 70 neck operations were performed over a 10-year
period from January 2004 to May 2013. See Table 1 for
patient demographic information. Table 2 contains informa-
tion regarding the preoperative radiographic nodal assess-
ment based on ultrasound and CT scan.
Salari et al 3

Table 1. Patient Demographics (N = 35).a Table 3. Measurements of Tumor Markers in Patients with
Differentiated Thyroid Cancers.
Characteristic No. (%)
Mean Mean
Women 26 (74.3) Preoperative Postoperative
Men 9 (25.7) Tumor Marker Value Value
Age (y), mean (range) 43 (13-84)
Pathologic diagnosis MTC
Papillary thyroid carcinoma 31 (88.6) Calcitonin, pg/mL 2927.0 42.2
Medullary thyroid carcinoma 4 (11.4) CEA, ng/mL 46.5 2.3
Stage PTC
I 20 (57.1) Nonstimulated Tg, ng/mL NA 0.2
II 2 (5.7) Stimulated Tg, ng/mL NA 0.75
III 1 (2.9)
Abbreviations: CEA, carcinoembryonic antigen; MTC, medullary thyroid carci-
IV 12 (34.3) noma; NA, not applicable; PTC, papillary thyroid carcinoma; Tg, thyroglobulin.
a
Values are presented as number (%) unless otherwise indicated.

patients (28.6%). Six (17.4%) patients had gross tumor inva-

Table 2. Preoperative Radiographic Nodal Assessment (N = 35). sion of the RLN on final pathology; 3 nerves were sacrificed
intraoperatively. Before sacrificing the RLN in these patients,
Left, Right, Midline, contralateral RLN was dissected to ensure its preservation
Characteristic No. (%) No. (%) No. (%) and functionality. As a result of this contralateral dissection,
excision of the contralateral thyroid and central neck dissection
Lateral neck compartments
(CND) were also carried out at the same time; the second stage
0 nodes 7 (20.0) 10 (28.6)
then consisted of contralateral lateral neck dissection (LND)
1-3 nodes 7 (20.0) 9 (25.7)
only. Strap muscles were sacrificed due to invasion in 12
.3 nodes 10 (28.6) 4 (11.4)
(34.3%) patients. Thirty-two patients (91.4%) had 3 or more
Multiple nodesa 13 (37.1) 14 (40.0)
positive lymph nodes, and 18 patients (51.4%) had extranodal
Bilateral involvement 22 (62.9)
spread. The mean numbers of positive and excised lymph nodes
Central neck compartments
per patient were 17.0 6 11.3 (range, 0-44) and 51.2 6 20.9
0 nodes 28 (80.0) 29 (82.9) 29 (82.9)
(range, 16-115), respectively, with a ratio of positive-to-excised
1-3 nodes 8 (22.9) 7 (20.0) 7 (20.0)
lymph nodes of approximately 1:3. The mean number of
.3 nodes 0 (0) 0 (0) 1 (2.9)
involved neck compartments was 3.6 6 1.5, and 12 patients
Multiple nodesa 1 (2.9) 1 (2.9) 0 (0)
(34.3%) had 5 or more involved compartments.
Bilateral involvement 3 (8.6)
a
In cases where the radiologist did not provide a total number of abnormal Complications, Adjuvant Therapies, and Follow-up
nodes and simply described them as ‘‘multiple,’’ they are counted as such. Three (8.6%) patients had intentional unilateral RLN sacri-
fice intraoperatively with resultant permanent RLN paraly-
sis; there were no cases of unintentional RLN injury.
Sixteen patients (45.7%) developed temporary hypopar-
athyroidism, and 1 patient (2.9%) had permanent hypopar-
Operative Data
athyroidism. One patient (2.9%) developed chyle leak
All surgeries were performed with RLN monitoring. The mean following the first operation. There were no other clinically
interval between the 2 stages was 10.9 6 3.7 weeks (range, 4- important complications.
25 weeks). Ten (28.6%) patients underwent autotransplantation Twenty-six patients (80.6%) with PTC received radioac-
of 1 or 2 parathyroid glands. All 4 patients with MTC had a tive iodine (RAI) therapy with mean dosage of 112.2 6
postoperative decrease in calcitonin and CEA levels, and 40.1 mCi, and 5 RAI-eligible patients either had no evi-
88.2% of patients with PTC had nonstimulated thyroglobulin dence of disease postoperatively or refused treatment. One
(Tg) \0.2 ng/dL nonstimulated thyroglobulin levels following patient (2.9%) received postoperative radiotherapy; she had
surgery; see Table 3 for further data. extensive locoregional spread of a sporadic MTC with per-
sistently elevated calcitonin levels following surgery; given
Histopathologic Data these findings, it was recommended that she undergo adju-
The mean maximum size of the primary thyroid tumor was vant external beam radiation. Mean follow-up period after
2.4 6 1.2 cm (range, 0.7-5.3 cm). Extrathyroidal invasion the second operation was 147 weeks (1.8 years), and all
was present in 25 patients (71.4%), and vascular invasion as except 7 patients had 2 or more years of follow-up.
noted in the surgical pathology was present in 18 (51.4%). At the time of this report, all patients were alive, and
The location of the primary tumor was bilateral in 10 locoregional recurrence had occurred in 2 (5.7%) patients,
4 Otolaryngology–Head and Neck Surgery
diagnosed at 22 and 55 months after the second operation.
Recurrence in these 2 patients was detected by means of
increasing thyroglobulin, abnormal ultrasound, and FNA.
Discussion
Optimum management of PTC and MTC requires appropriate
clearance of affected and at-risk cervical lymph nodes.16,21
Lymph node metastases in PTC are associated with increased
recurrence rate and, in some patient subsets, lower disease-
specific or overall survival.22 Thorough surgery at presentation
may improve outcome and prevent recurrence. However, bilat-
eral central and lateral neck dissections for extensive bulky,
widely distributed nodal metastases carry a significant risk of
complications. In the central neck, total thyroidectomy and
simultaneous extensive bilateral CND have been associated
with higher rates of RLN injury and hypoparathyroidism com-
pared with similar unilateral procedures.23 Simultaneous dis-
section of bilateral lateral cervical compartments can increase
postoperative complications due to jugular vein sacrifice-
cerebral edema, cranial nerve injury, postoperative bleeding,
increased pain, and chyle leak.24 Staged surgery should be an
acceptable management choice in the setting of significantly
advanced, extensive, and widely distributed nodal disease
given the typically slow progression of differentiated thyroid
carcinoma and the relatively short extension of the treatment
time. In the setting of locoregionally advanced thyroid cancer,
staged surgery may decrease the risk of complications in
patients requiring extensive dissection of lateral and central
compartments.
Staged central neck surgery can avoid bilateral RLN paraly-
sis, which is the core rationale for the staged approach, and
hypoparathyroidism by allowing a neuropraxic RLN to regain
function and ipsilateral ischemic in situ or autotransplanted
parathyroid glands functional status improvement prior to the
contralateral procedure. In a review of patients with benign
and malignant thyroid pathology, hypocalcemia was more
common after simultaneous bilateral surgery compared with 2-
stage surgeries, suggesting recovery of any impairment in
parathyroid function between the 2 operations.25 The safety of
completion thyroidectomy compared with primary total thyroi-
dectomy also has been shown previously.26
Many meta-analyses have been published with disagree-
ing conclusions on IONM.27,28 Zheng et al27 showed that a
decrease in rates for transient VCP was statistically signifi-
cant while that in permanent VCP was not. Other meta-
analyses reported that the reductions in both transient as
well as permanent VCP rates with IONM were not statisti-
cally significant.28,29 Some publications have shown that
IONM is associated with a lower RLN injury rate.30,31 Most
recently, Bergenfelz et al32 reviewed the Scandinavian
Quality Register to study 5252 thyroidectomy patients with
IONM applied in 60% patients and concluded that IONM
was associated with a decreased risk of permanent VCP.
Intraoperative laryngeal palpation during RLN stimulation
is a safe, reliable method that can not only assist in RLN
identification and assessment during surgery but can also
assist in troubleshooting during IONM for RLN when loss
of signal (LOS) is noticed.33
Incorporation of IONM findings into surgical planning for
bilateral thyroid procedures is a relatively new application of
IONM. Routine RLN monitoring allows for intraoperative
flexibility in surgical strategy by providing feedback on LOS
on the initial side of resection. The decision can be made
intraoperatively to pursue 2-stage surgery following LOS to
avoid bilateral RLN paralysis, a highly morbid complication
of thyroid surgery.34,35 Goretski et al34 found that the rate of
bilateral nerve injury was 17% when RLN monitoring for
LOS was not incorporated into the surgical strategy and zero
when monitoring information was used. This strategy has
been shown to be acceptable among surgeons and does not
compromise patient satisfaction.35 Rarely with extensive
neural dissection, there may be false-negative results (ie, no
LOS but postoperative VCP), and patients should be appro-
priately counseled regarding the benefits and limitations of
RLN monitoring during procedures for extensive disease.36
Surgical Outcomes
We reviewed the recent PTC cancer literature and analyzed
series of PTC patients by stage, complication, and oncologic
outcome data. Our outcomes compare favorably with these
historical controls despite limitations due to variation in dis-
ease pathology, surgical approach, and available data (see
Table 2). This was particularly evident when considering the
proportion of patients in the current series with advanced dis-
ease. The average stage in our series is significantly more
advanced than in any series available in the literature. For
example, the national Surveillance, Epidemiology, and End
Results (SEER) database reported a 30% rate of nodal metas-
tases compared with our series with a 97% rate of nodal
metastases.37
In reviewing this literature, the rate of permanent RLN
paralysis is up to 3.6% for surgeries performed for thyroid
cancer.38 In the present study, there were no cases of RLN
paralysis as an unintentional complication of surgery, and
no patients required tracheotomy. In addition, although 28%
of patients in our series underwent parathyroid gland auto-
transplantion, a permanent hypoparathyroidism rate of 2.9%
in the current series is at the lower end of the currently pub-
lished data of about 2% to 16%.23,26,39
Longer operative length has been suggested to cause sur-
geon muscular fatigue.40 A study of a series of lumbar
fusion surgery suggested that longer operative duration was
a risk factor for postoperative complications.41
Oncologic Outcomes
Historically, the risk of recurrence in stage I PTC is up to
10%, while the recurrence rates for stage II and III disease
are 20% and 30%, respectively.42 In the present study, the
overall recurrence rate was 5.7% (median follow-up, 28
months) despite 37% of patients presenting with stage III or
IV disease. In a series reported by the Mayo Clinic, the
recurrence rate was 11% despite significantly lower stage of
Salari et al
disease in the patients involved.43 A recent ATA review of
the world literature showed that the rate of locoregional
lymph node recurrence is about 22% in clinically node-
positive patients.44
Limitations and Future Directions
The main limitation of the present study is that this is a
single-institution, single-cohort, retrospective, nonrando-
mized study with a small sample size with relatively short
follow-up. However, this study does provide a useful frame-
work for discussion of the role of planned staged surgery in
the treatment of advanced thyroid malignancy. Another
shortcoming is that since this is a surgical feasibility study
conducted in a small sample with 2 biologically different
pathologies (MTC and PTC) with relatively short follow-up,
the overall success of locoregional control should be
asserted cautiously. While a staged approach is a feasible
option for such advanced thyroid cancers, performing 2 pro-
cedures will increase overall cost. Future studies should
assess patient selection criteria, proper timing of the 2 surgi-
cal stages, and a cost-benefit analysis of planned staged sur-
gery. This approach is optimally considered for thyroid
cancer surgeons for management of patients presenting with
very extensive disease and would not be applicable to prac-
tices managing less extensive disease at presentation.
Conclusion
Neural monitored, staged neck surgery for advanced thyroid
malignancy can be conducted without significant adverse
events in this small sample and can be considered an alter-
native to simultaneous bilateral operation, as staged neck
surgery in our series is associated with low surgical compli-
cations and acceptable oncological outcomes. It may repre-
sent an effective strategy to improve quality of life
postoperatively by decreasing the risks of bilateral RLN
paralysis, hypocalcemia, and other complications. In addi-
tion, shortening the duration of a single surgery may benefit
both the surgeon, by increasing attentiveness, and the
patient, by avoiding the risks of lengthy general anesthesia.
Further studies are needed, but neural monitored, staged
neck surgery is a promising surgical approach for the man-
agement of advanced thyroid malignancy.
Author Contributions
Behzad Salari, acquisition of data or analysis of data, drafting and
revising the article; Rebecca J. Hammon, conception and design,
data analysis and interpretation, drafting and revising article; Dipti
Kamani, conception and design, analysis and interpretation of
data, drafting the article or revising it critically for important intel-
lectual content; Gregory W. Randolph, conception and design,
analysis and interpretation of data, revising the manuscript criti-
cally for important intellectual content.
Disclosures
Competing interests: None.
Sponsorships: None.
5
Funding source: John and Claire Bertucci Thyroid Research
fund.
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