Received: 2 February 2017

| Revised: 19 July 2017

| Accepted: 3 September 2017
DOI: 10.1002/hed.24969

ORIGINAL ARTICLE

Management of the lateral neck compartment in patients with

sporadic medullary thyroid cancer

Israel Pena MD1 | Gary L. Clayman MD1 | Elizabeth G. Grubbs MD2 |

Jeffrey M. Bergeron Jr BS1 | Steven G. Waguespack MD3 |
Maria E. Cabanillas MD3 | Ramona Dadu MD3 | Mimi I. Hu MD3 |
Bryan M. Fellman MS4 | Yisheng Li PhD4 | Neil D. Gross MD1 |
Stephen Y. Lai MD, PhD1 | Erich M. Sturgis MD1 | Mark E. Zafereo MD1

1
Department of Head and Neck Surgery,
Abstract
MD Anderson Cancer Center, Houston,
Texas Background: The purpose of this retrospective analysis was to evaluate the benefits
2
Department of Surgical Oncology, MD of an elective lateral neck dissection (ELND) in patients with medullary thyroid can-
Anderson Cancer Center, Houston, Texas cer (MTC) without radiographically apparent lateral neck metastases.
3
Department of Endocrine Neoplasia and
Methods: Patients with sporadic MTC without radiographic evidence of lateral neck
Hormonal Disorders, MD Anderson
Cancer Center, Houston, Texas metastasis who underwent definitive surgery were divided into 2 groups based on
4
Department of Biostatistics, MD
surgical approach: no ELND (the observation group) and ipsilateral or bilateral
Anderson Cancer Center, Houston, Texas ELND (the ELND group). Primary outcomes were biochemical cure, locoregional
recurrence, distant metastasis, and overall survival (OS).
Correspondence
Results: Sixty-six patients met inclusion criteria: 44 patients (67%) in the observa-
Mark E. Zafereo, Department of Head
and Neck Surgery, The University of
tion group and 22 patients (33%) in the ELND group. Two of 44 patients (5%) in the
Texas MD Anderson Cancer Center, observation group developed subsequent (ipsilateral) lateral neck disease. At last
1515 Holcombe Boulevard, Houston, TX follow-up, locoregional disease control rates among the observation and ELND
77030. groups were 98% and 100% (P > .999), respectively, whereas biochemical cure rates
Email: [email protected] were 82% and 85% (P > .999), respectively, and 5-year OSs were 84% and 100% (P
5 .156), respectively.
Conclusion: Patients with MTC without lateral neck metastasis have similar bio-
chemical cure rates with observation or elective dissection of lateral neck
compartments.

KEYWORDS
American Thyroid Association, calcitonin, elective neck dissection, observation, regional metastases

1 | INTRODUCTION
This study was presented as an oral presentation at the AHNS Ninth
International Conference on Head and Neck Cancer, Seattle, Washington, The standard treatment for patients with sporadic medullary
July 16-20, 2016 (S333). thyroid cancer (MTC) and no preoperative or intraoperative
Ehab Y. Hanna, MD, Editor, was recused from consideration of this diagnosis of nodal metastasis is total thyroidectomy and elec-
manuscript. tive central neck dissection, based on the American Thyroid

Head & Neck. 2017;1–7. wileyonlinelibrary.com/journal/hed V

C 2017 Wiley Periodicals, Inc. | 1
2 | PENA ET AL.

Association (ATA) and the British Thyroid Association imaging. The postoperative serum calcitonin and carcinoem-
(BTA) guidelines.1,2 The surgical management of the lateral bryonic antigen (CEA) levels at approximately 3 months
neck compartment in patients without imaging-proven diag- (and up to 6 months) after surgery were considered the post-
nosis of lateral neck disease after thorough cervical imaging, operative baseline. To meet the purpose of this study,
however, is controversial. Based on the increased risk of lat- patients who had lateral neck disease on preoperative imag-
eral compartment metastasis with increasing T classification ing were excluded. Additional exclusion criteria included
and palpable lymph nodes,3,4 the 2007 BTA guidelines rec- patients with concurrent nonthyroid malignancies.
ommended a bilateral elective lateral neck dissection Patients were divided into 2 groups based on surgical
(ELND) for all patients with T2-T4 disease or those with pal- approach. The observation group had no ELND, and the
pable lymph nodes in the central or lateral neck.5 These rec- ELND group had an elective ipsilateral or bilateral LND.
ommendations have been adjusted in the newest 2014 BTA Variables collected from each patient included demo-
guidelines, which now recommend an ipsilateral ELND only graphics, preoperative imaging, TNM classification, initial
in patients who have central neck disease.2,6 Based on an and subsequent calcitonin and CEA measurements, date and
increased risk of ipsilateral lateral neck disease beginning at extent of surgery, and follow-up disease status.
a calcitonin level of 20 pg/mL, and contralateral lateral neck Demographic and clinical characteristics were compared
disease beginning at a calcitonin level of 200 pg/mL,7 the between treatment groups using the chi-square, Fisher’s
2015 ATA guidelines recommend consideration of an ipsilat- exact, or Wilcoxon rank sum tests. Biochemical cure was
eral ELND when calcitonin is 20 pg/mL and a bilateral defined as postoperative calcitonin 10 pg/mL at 3-6 months
ELND when calcitonin is 200 pg/mL.1 after surgery. Locoregional recurrence was defined as recur-
The addition of a lateral neck dissection (LND), how- rence within the thyroid bed, central compartment, or lateral
ever, potentially increases operative time, cost, and, most compartment based on radiographic imaging. Final locore-
importantly, patient morbidity, including additional surgical gional disease status was defined as radiographic evidence of
risks, such as chyle leak, hematoma, or injury to neurovascu- locoregional recurrence at last follow-up, and distant metas-
lar structures. To date, the benefit of performing an ELND in tasis was defined as radiographic evidence of distant disease.
cases with no preoperative radiographic lateral neck disease Biochemical cure, locoregional recurrence, locoregional dis-
has not been clearly demonstrated. The purposes of this anal- ease, and distant metastasis were compared between groups
ysis were to evaluate the biochemical cure, locoregional using the chi-square or Fisher’s exact tests. The OS was esti-
recurrence, distant metastasis, and overall survival (OS) in mated within each group using the Kaplan-Meier product-
patients with no radiographically apparent lateral neck dis- limit estimator, and a log-rank test was used to compare the
ease (cN0-cN1a) who undergo an ELND, and compare them survival functions between surgical approaches. The OS was
with patients who are managed with observation of the lat- calculated as the time from surgery to the date of last follow-
eral neck. up or death. Statistical significance was assessed at a 2-sided
0.05 level.
2 | MATERIALS AND METHODS
3 | RESULTS
After obtaining intuitional review board approval, a retro-
spective review was performed of patients diagnosed with A total of 66 patients met inclusion criteria. Forty-four
MTC between June 1992 and October 2014 at The Univer- patients (67%) had no LND (the observation group), and 22
sity of Texas MD Anderson Cancer Center. Patients with patients (33%) had an elective LND (the ELND group). Of
MTC who had definitive surgery at MD Anderson Cancer the 22 patients in the ELND group, 4 (18%) underwent bilat-
Center, to include total or completion thyroidectomy and eral ELND.
central neck dissection with or without ipsilateral or bilateral Table 1 compares demographic and clinical characteris-
lateral neck dissection, were included. Surgeries were per- tics between the 2 groups. The majority of patients were
formed by 9 surgeons in either the department of head and women (64%) with a median age of 53 years (range 15-85
neck surgery or the department of surgery after a consensus years). Median follow-up for the entire cohort of 66 patients
in management at the endocrine multidisciplinary confer- was 3.9 years and was significantly different between the
ence. Patients determined to have hereditary MTC by germ- observation (2.3 years; 0.1-13.4) and the ELND groups (9.0
line mutations of the rearranged during transfection (RET) years; 1.0-17.0; P < .001). The median year of surgery in
proto-oncogene were excluded in order to include only the ELND group was 2004, compared to 2011 for the obser-
patients with sporadic MTC. All patients had preoperative vation group (P < .001). Preoperative imaging (ultrasound
ultrasound (including evaluation of the thyroid bed, central and/or CT) was performed in all 66 patients. In the observa-
compartment, and bilateral lateral necks) and/or CT neck tion group, 98% of patients had preoperative ultrasound,
PENA ET AL.
| 3

T A BL E 1 Characteristics among patients with medullary thyroid carcinoma with no preoperative lateral neck disease (N 5 66)

Variables Observation group ELND group P value

Unique patients 44/66 (67%) 22/66 (33%) ...

Female sex 28/44 (64%) 13/22 (59%) .720

Age, median years (range) 55 (25-85) 49 (15-78) .446

Follow-up, median years (range) 2.3 (0.1-13.4) 9 (1-17) < .001

Surgery date, median year 2011 2004 < .001a

Preoperative CT or ultrasound 44/44 (100%) 22/22 (100%) ...

Preoperative ultrasound 43/44 (98%) 18/22 (82%) .039
Preoperative CT 29/44 (66%) 16/22 (73%) .575

T classification ... ... .161

T1 17/44 (39%) 3/22 (14%) ...
T2 14/44 (32%) 9/22 (41%) ...
T3 11/44 (25%) 8/22 (36%) ...
T4 2/44 (5%) 2/22 (9%) ...

N classification ... ... > .999

N0 39/44 (89%) 20/22 (91%) ...
N1a 5/44 (11%) 2/22 (9%) ...
N1b 0/44 (0%) 0/22 (0%) ...

M classification ... ... .549

M0 42/44 (96%) 22/22 (100%) ...
M1 2/44 (5%) 0/22 (0%) ...

Preoperative CTN >20 pg/mLb 38/41 (93%) 19/20 (95%) > .999

Preoperative CTN >200 pg/mLb 28/41 (68%) 19/20 (95%) .024

b
Preoperative CTN pg/mL, median (range) 714.0 (1-10 472) 1243.7 (6-14 900) .016

Preoperative CEA ng/mL, median (range)b 17.9 (0-502.7) 60.5 (0-265.7) .365

Postoperative CTN pg/mL, median (range)c 1.0 (1-463) 1.0 (1-355) .737
c
Postoperative CEA ng/mL, median (range) 1.4 (0-6.6) 1.4 (0-11.9) .498

Abbreviations: CEA, carcinoembryonic antigen; CTN, calcitonin; ELND, elective ipsilateral or bilateral lateral neck dissection group.
a
Calculated as difference in time between reference point (initial inclusion date of study January 1, 1992) and surgery date.
b
Three patients in the observation group and 2 patients in the ELND group did not have preoperative CTN data available. Similarly, 3 patients in the observation
group and 5 patients in the ELND group did not have preoperative CEA data available. The postoperative serum CTN and CEA levels at approximately 3 months
after surgery were considered the postoperative baseline.

versus 82% in the ELND group (P 5 .039). Per design, all preoperative CEA levels were 18 pg/mL (range 0-503 pg/
patients in the observation and ELND groups had no preop- mL) and 61 pg/mL (range 0-266 pg/mL; P 5 .365), respec-
eratively diagnosed lateral neck disease, and there was no tively. Thirty-eight of 41 patients (93%) in the observation
difference in T classification (P 5 .161) or N classification group had calcitonin 20 pg/mL, and 28 of 41 patients
(P > .999). The observation group had 2 of 44 patients (5%) (68%) had calcitonin 200 pg/mL.
with distant metastases at initial presentation compared to 0 There was no difference in the rate of central neck dis-
of 22 patients (0%) in the ELND group, but this difference ease on final pathology among the observation (27%) and
was not significant (P 5 .549). The median preoperative cal- ELND (36%) groups (Table 2). However, 32% of patients (7/
citonin levels among the observation and ELND groups were 22) in the ELND group had lateral neck disease, all ipsilat-
714 pg/mL (range 1-10 472 pg/mL) and 1244 pg/mL (range eral, on final pathology despite not having any radiographic
6-14 900 pg/mL; P 5 .024), respectively, and median evidence of lateral neck disease on preoperative imaging.
4 | PENA ET AL.

T A BL E 2 Postoperative regional disease burden based on surgical Similarly, there was no difference in survival between the 2
pathology (N 5 66) groups (Supporting Information Figure S1). Only 2 patients
(5%) in the observation group developed subsequent ipsilateral
Variables Observation group ELND group
neck disease. One of these patients had a preoperative calcito-
Central neck disease 12/44 (27%) 8/22 (36%) nin of 664 pg/mL, postoperative calcitonin of 8 pg/mL, devel-
Positive lateral ... 6/8 (75%)a oped ipsilateral lateral neck disease at 10 months, had
neck disease ipsilateral lateral neck surgery, and remained without evidence
No central neck disease 32/44 (73%) 14/22 (64%) of disease at last follow-up. The second patient had unknown
Positive lateral ... 1/14 (7%)a
preoperative calcitonin, postoperative calcitonin of 463 pg/mL,
neck disease developed both ipsilateral neck disease and distant metastases
at 7 months, and was not recommended for lateral neck sur-
Ipsilateral lateral ... 7/22 (32%) gery because of a significant burden of systemic disease.
neck disease
Therefore, this patient was the only patient in the observation
Positive central ... 6/7 (86%)b group who had locoregional disease at last follow-up. One
neck disease
patient in the ELND group had subsequent ipsilateral lateral
No ipsilateral lateral ... 15/22 (68%) neck recurrence, which was successfully salvaged with a sec-
neck disease ond ipsilateral lateral neck dissection. Therefore, no patients in
Positive central ... 2/15 (13%)b the ELND group had locoregional disease at last follow-up.
neck disease Two patients in the observation group had preoperative
evidence of distant metastasis, and 2 additional patients sub-
Contralateral lateral ... 0/4 (0%)
neck disease
sequently developed distant metastasis. In comparison, no
patients in the ELND had preoperative distant metastasis,
Abbreviation: ELND, elective ipsilateral or bilateral lateral neck dissection
and 1 patient in this group subsequently developed distant
group.
a
Indicates a statistically significant (P 5 .002) difference in positive lateral
metastasis. The rate of development of distant metastasis
neck disease among patients in the ELND group with central neck disease after surgery was, therefore, equivalent between groups (2/
compared with those with no central neck disease. 42; 5% in the observation group, and 1/22; 5% in the ELND
b
Indicates a statistically significant (P 5 .004) difference in positive central
group).
neck disease among patients in the ELND group with lateral neck disease com-
pared with those with no lateral neck disease.
Five patients died of disease in the observation group,
and 3 patients died in the ELND group. Of the 5 who died in
the observation group, 2 died of disease, both patients with
One of these 7 patients with lateral neck metastasis had a
extensive distant metastases, 1 of whom had known meta-
neck dissection, which did not differentiate among neck lev-
static disease before thyroid surgery. The other 3 patients in
els. Among the other 6 patients, level 4 was the most com-
the observation group who died were without evidence of
mon site of lateral neck metastasis (5/6) followed by level 3
disease at the time of their death. The 3 patients in the
(3/6) and level 2 (2/5).
ELND group who died were all without evidence of disease
Patients with lateral neck disease were more likely to
at the time of their death. There was no difference in OS
have central neck disease (86%), compared with patients
between treatment groups (log-rank P 5 .156).
without lateral neck disease (13%; P 5 .004). The opposite
was also true; patients with central neck disease were more
likely to have lateral neck disease (75%) than those without 4 | DISCUSSION
central neck disease (7%; P 5 .002). None of the 4 patients
(0%) in the ELND group who underwent bilateral elective The management of the lateral neck in patients with MTC
neck dissections had contralateral neck disease. Among confined to the central neck, as determined by preoperative
patients in the ELND group, there was no significant differ- imaging is controversial, with discrepancies between the
ence in the median preoperative calcitonin among patients ATA and BTA recommendations.1,2 Although a 20% or
who had lateral neck disease (n 5 2951) and those who did greater risk of occult metastasis for head and neck squamous
not have lateral neck disease (1165; P 5 .336). The only cell carcinoma is the accepted threshold for performing an
complication specific to a lateral neck dissection was a chyle elective neck dissection,8 there is no clear evidence as to
leak in 1 patient (5%). what threshold risk of MTC warrants an ELND. Several
There were no differences in biochemical cure, locore- studies have stratified the risk of lateral neck metastasis of
gional recurrence, locoregional disease status, or distant metas- MTC based on basal preoperative serum calcitonin levels, T
tasis when stratifying patients according to observation versus classification, or presence of palpable disease.4,7,9 These
elective dissection of the lateral compartment (Table 3). studies, however, included a more heterogeneous group of
PENA ET AL.
| 5

T A BL E 3 Outcomes among patients with no preoperative lateral neck disease (N 5 66)

Variables Observation group ELND group P value

Biochemical curea 32/39 (82%) 17/20 (85%) > .999

Locoregional recurrence 2/44 (5%) 1/22 (5%) > .999

Final locoregional disease status 1/44 (2%) 0/22 (0%) > .999

Distant metastasis 4/44 (9%)b 1/22 (5%) > .999

5-y OS 0.84 (0.64-0.94) 1.00 (NE) .156c

10-y OS 0.84 (0.64-0.94) 0.93 (0.61-0.99) .156c

Abbreviations: ELND, elective ipsilateral or bilateral lateral neck dissection group; NE, not evaluable; OS, overall survival.
a
Postoperative calcitonin unavailable for 5 patients in the observation group and 2 patients in the ELND group.
b
Two of these 4 patients had known distant metastasis before their initial thyroid surgery, such that the interval rate of distant metastasis is 2/42 (5%).
c
The P value compares the OS function between groups using the log-rank test.

patients with MTC and did not specifically investigate popu- majority of patients with MTC without potential worsening
lations with no known preoperative lateral neck disease. in recurrence and survival outcomes.
Data in the current study suggest that, among patients Although this study suggests that observation of the lat-
with no known preoperative lateral neck disease, the risk of eral neck in patients with no preoperatively diagnosed lateral
occult lateral neck disease may not be sufficient to warrant neck disease is a reasonable approach, it remains unclear if
an ELND. Patients in our study without evidence of lateral there is a threshold of risk of lateral neck disease where an
neck disease on preoperative imaging did not receive any ELND would be warranted. Machens et al6 showed that the
benefit in the rates of biochemical cure, locoregional recur- presence of central neck disease increased the risk of lateral
rence, distant metastasis, or OS with an ELND. Among neck disease in the general patient with MTC population.
patients whose lateral compartments were observed (the We found similar results in patients without known preopera-
observation group), the small minority of patients (5%) who tive lateral neck disease. In the group of patients who under-
later developed lateral neck disease had opportunity for an went an ELND, the presence of central neck disease
LND at a future time without an appreciable negative impact increased the risk of occult lateral neck disease to 75%. We
on overall outcome. Only 1 patient (2%) in the observation were, however, unable to evaluate outcomes in this patient
group has thus far undergone an LND, leaving this patient population due to the small sample size of patients with cen-
with no evidence of locoregional disease; whereas a second tral neck disease who underwent an ELND.
patient with locoregional recurrence was not recommended An inherent limitation of this study is the retrospective
for LND due to progression of widely metastatic disease. design and the potential selection bias between patients
This compares to 93% of patients in the observation group managed with observation versus ELND. There has been a
who may have been considered for an ELND according to trend toward observation of the lateral neck at our institu-
ATA guidelines, which recommend consideration for an ipsi- tion, as evidenced by the significantly later median surgery
lateral ELND when calcitonin is 20 pg/mL.1 Furthermore, date in those patients whose lateral neck compartments
70% of patients in the observation group may have been con- were observed. Therefore, the median follow-up time in the
sidered for bilateral ELND according to ATA guidelines, more recent group whose lateral compartments were
which recommend consideration of bilateral ELND when observed was significantly less than patients who had an
calcitonin is 200 pg/mL.1 ELND and is a limitation in extrapolating the results of this
Although the morbidity of LND in this study was low, study. Longer follow-up time will be important to confirm
with only 1 patient in the ELND group having a complica- that the locoregional recurrence and survival trends main-
tion of a chyle leak (5%), it is known that lateral neck dissec- tain equivalence. However, biochemical cure, which pre-
tion increases the morbidity of surgery. Specifically, the risk dicts a survival rate of 98% at 10 years, remains equivalent
of chyle leak increases from 1.4% with a central neck dissec- between the 2 groups and was not affected by this differ-
tion alone to 8.3% with a LND, and LND carries the poten- ence in follow-up time.13
tial for up to 44% risk of shoulder dysfunction.10–12 By Finally, it is known that age, stage, number of positive
performing an LND only in the setting of locoregional recur- regional lymph node metastases, preoperative serum CEA,
rence to the lateral neck instead of an ELND, the morbidity perioperative serum calcitonin levels, and doubling time of
of this additional procedure may be eliminated in the postoperative serum calcitonin levels are all prognostic
6 | PENA ET AL.

indicators for patients with MTC.6,7,13–20 Although there was Erich M. Sturgis MD http://orcid.org/0000-0002-1069-
no significant difference in age, stage, preoperative serum 4822
CEA, and preoperative serum calcitonin >20 pg/mL between mark zafereo MD http://orcid.org/0000-0001-7918-9739
the groups, the preoperative median calcitonin was noted to
be significantly higher in those who underwent an ELND. R EFE RE NC ES
However, because this could be a potential confounder in
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| 7

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