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of central node metastases in the neck. With
one to nine positive nodes in the central
compartment, contralateral lateral neck
involvement increased from 5 to 38 %, reaching 77% with 10 or more positive central
nodes [121]. For patients with intensive central neck involvement, microdissection of the
central and both lateral neck compartments
is recommended.
4. Lymph node metastases have not been
observed in the infrabrachiocephalic upper
mediastinum with small primary tumors up
to a tumor diameter of 10 mm [14]. Like
lateral node metastases in the contralateral
neck, mediastinal node metastases also occur
at the same time as distant metastases [121,
122]. Because of this coincidence with
systemic disease, the clinical benefit of transsternal mediastinal LND, without any evidence of mediastinal disease, is too small to
warrant its routine use.
5. Sporadic and hereditary MTC do not differ
from each other in metastatic behavior (lymphangic, hematogenous) when they have the
same tumor stage [114, 120]. The required
extent of dissection is largely determined by
oncologic features, such as multiple primary
tumors, which are typical of hereditary disease, and neck node metastases, which tend
to be more advanced in sporadic disease for
which early screening is less cost-effective
and less widespread.
6. In hereditary disease, most of which is identified through early screening, the timing of
prophylactic thyroidectomy and the extent of
lymph node surgery are based more on preoperative calcitonin levels than on any other
piece of information including type of RET
mutation or preoperative ultrasound findings. The so far largest studies from the Euromen Study Group [123–125], the French
GETC Study Group [126], and smaller series
from Germany and Austria [127], Halle [128,
129], St. Louis [65], and Houston [130]
revealed the critical function of lymph node
metastases in achieving cure, which play a far
more important role than the primary
tumors, the originators of lymphatic dissemination. Especially when they are small,
lymph node metastases cannot always be
identified, neither by high-resolution cervical ultrasonography nor by visual inspection,
direct palpation or frozen section during the
operation. In this setting, determination of
preoperative basal calcitonin levels is useful
to identify those carriers who have not yet
developed lymph node metastases. Based on
literature data [125, 126] and personal
experience, lymph node metastases are not
present in gene carriers who still have normal
basal calcitonin levels. It is therefore reasonable to perform compartment-oriented LND
in previously untreated gene carriers with
abnormal basal calcitonin levels but not in
those with normal basal calcitonin levels
[131].
7. In clinically apparent MTC, systemic disease
is common. In occult MTC, laparoscopy
[132], bone scintigraphy and MRI [133],
liver angiography [134], FDG-PET scanning
[50], and selective venous sampling of calcitonin [135] are able to uncover distant
metastases as the source of persistent hypercalcitoninemia. In clinical practice, these
sophisticated techniques can help one to
plan reoperations more adequately, sparing
patients with occult MTC an odyssey through
many hospital departments with repeated
imaging and frequent reoperations.
8. With the introduction of the technique of
compartment-oriented microdissection,
locoregional reoperations now result more
often in the normalization of postoperative
calcitonin levels [24, 136–139]. Indicative of
surgical cure, this biochemical normalization
is widely taken as a measure of surgical success. Because locoregional recurrence frequently acts as the ‘‘pacemaker’’ of disease,
even extensive procedures are justified when
they provide symptomic relief [111, 119].
9. Despite some improvements in recurrencefree and overall survival, biochemical cure
rates remain unsatisfactory, especially for
node-positive MTC patients (10–20%).
Locoregional lymph node metastases and
distant metastases represent the largest
obstacle to normalization of serum calcitonin levels. With more than 10 lymph node
metastases, and more than two involved
compartments, biochemical cure is exceptional due to concomitant distant metastases [32, 117]. Early detection through
calcitonin screening and adequate surgery
based on the compartment-oriented dissection technique remain decisive factors of
cure [140–142].
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LYMPH NODE DISSECTION IN THYROID CANCER
Surgical Techniques of Lymph
Node Dissection
A recent study [143] suggested that as many as
75% of reoperations for persistent or recurrent
PTC might have been preventable if the initial
operation had followed applicable practice
guidelines. Root cause analysis revealed that
mainly the extent of initial LND had been inadequate, much more often than the extent of thyroid resection which accounted for only 25% of
inadequate procedures. Likewise, a significant
proportion of patients with gross MTC continue
to receive substandard treatment. Based on US
SEER data, 15%of MTC patientsreceive less than
total thyroidectomy, and 41% of MTC patients
with stage IV disease have no LND whatsoever
[144]. Although no comparable data exist for the
other types of thyroid cancer, it is reasonable to
assume that the failure to adequately dissect cervical lymph nodes is a major cause of locoregional failure in patients with thyroid cancer,
prompting even more operations at the cost of
additional morbidity.
Significant progress in preoperative work-up
and the development of the technique of compartment-oriented microdissection [24, 117, 136,
137, 145–147] have resulted in more adequate
initial operations for thyroid cancer. Several
techniques of lymphnode management are available to address the wide range of node metastasis
from low-risk single-node to high-risk multiplenode involvement: sentinel node technique,
focused approach, regional LND including excision of single nodes (‘‘berry picking’’), and compartment-oriented microdissection.
Sentinel Node Technique
A multitude of studies have appeared over the
past decade dealing with the feasibility and
accuracy of the sentinel node technique for differentiated thyroid cancer [148–158]. These studies reported a substantial rate of false-positive
and, even more often, false-negative results
[159, 160]. The high variability of lymphatic
drainage in more than one direction and the
frequent existence of multiple primary thyroid
tumors render the sentinel node approach
unsuitable for routine use in patients with thyroid cancer outside a research setting.
Focused Approach
For a carefully selected subset of patients with
recurrent thyroid cancer, the focused approach
through a small skin incision may be appropriate
as a minimum procedure. As in any targeted
intervention, the focused approach requires a
valid surgical target that must have been identified before or, at the latest, during the operation
[161]. Various techniques have been developed
to guide the excision of that target, including
radioiodine-directed probes [162, 163], hook
needles [164], and high-resolution ultrasonography [161, 165, 166]. The latter two techniques
also work for recurrent radioiodine-negative differentiated and medullary thyroid cancer. As a
matter of principle, a focused approach is not
indicated for recurrent thyroid cancer with
tumor deposits at multiple sites.
Regional Lymph Node Dissection
Including Excision of Single Nodes
(‘‘Berry Picking’’)
Like the focused approach, the excision of single nodes (‘‘berry picking’’) may be suitable
for some patients who previously underwent
compartment-oriented LND for low-risk thyroid cancer and now require reoperations for
locoregional recurrence in the dissected area.
For cosmetic reasons, the neck should preferably be entered through a previous skin incision after excision of the scar. Neither
approach is recommended for the initial clearance of positive nodes [167]. As a general rule,
gross node metastases from MTC and PTC are
surrounded by occult node metastases, all of
which can be dispersed across more than one
region. If not cleared entirely, they are a frequent source of recurrence. For these reasons,
the single-node and single-region approach
have been largely abandoned [168].
Compartment-Oriented
Microdissection
Compartment-oriented microdissection [24] is
the standard procedure for node-positive thyroid cancer. It can involve one or more compartments. While, mainly advocated for surgery
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with curative intent, compartment-oriented
microdissection can also be effective in maintaining local control in patients with stable systemic disease. Depending on the clinical
context, the dissection may progress from the
lateral compartment(s) toward the central compartment (centripetal approach) or vice versa
(centrifugal approach). Upon preoperative evidence of locally advanced thyroid cancer in a
previously untreated patient, the centripetal
approach is the procedure of choice at the
authors’ institution. In the absence of such confirmation, the operation starts at the central
neck compartment, which is removed together
with the thyroid gland as one contiguous surgical specimen. Upon histopathological confirmation of cancer, the dissection proceeds to the
lateral neck compartments, one or both of
which are cleared as needed.
As elsewhere in the body, solid organs are
embedded in fibrofatty tissue. Containing arteries,
veins, and the lymphatic system including the
locoregional nodes, this fibrofatty tissue fills the
space between these organs. The concept of compartment-oriented microdissection is to dissect
the compartmental fatty tissue as one contiguous
surgical specimen to ensure that all locoregional
nodes are removed whereas vessels, nerves, and
muscles (other than strap muscles) are preserved.
This way, the compartment-oriented approach
provides for the elimination of extranodal tumor
deposits from the neck [169, 170].
As outlined above, the central neck compartment is limited dorsally by the trachea with the
thyroid gland and laterally by the medial aspect
of the common carotid arteries. Anatomical
landmarks thus delineate the borders of the
central neck compartment. Conversely, no
such landmarks exist to mark off the lateral
neck and the mediastinal compartment medially from the pharyngeal and laterally from the
nuchal, axillary and middle mediastinal nodes,
respectively.
The surgical technique of compartmentoriented microdissection in the neck and mediastinum has been described repeatedly in
surgical textbooks [171, 172]. The key elements
of this technique can be summarized as follows.
Central Neck Compartment
Whenever there is evidence of extrathyroidal
extension of thyroid cancer, the strap muscles
are removed together with the central lymph
node compartment (and the thyroid gland, if
not yet resected) as one contiguous surgical
specimen. At first surgery, the thyroid gland is
removed as a whole together with the right
andleftportionsofthecentralneckcompartment. For oncological reasons, the thyroid
gland is not divided at the isthmus, nor is it
separated from its adjacent fatty tissue, which
encloses the central lymph nodes (Fig. 13.2).
The central neck dissection includes the paratracheal nodes both ventral and dorsal to the
recurrent laryngeal nerve. These nodes may
be a cause of recurrent laryngeal nerve palsy
in node-positive thyroid cancer. The upper
parathyroid glands often are preserved in
situ, whereas this is unfeasible most of the
time for the lower parathyroid glands. Submental and submandibular nodes are routinely dissected in MTC but not in PTC.
Lateral Neck Compartment
Starting at the lateral aspect of the jugular vein,
the dissection is carried forward toward the
venous angle. Divided lymphatic vessels are
meticulously ligated, especially on the left side,
to prevent lymphatic leakage at the venous
angle from injuries to the thoracic or right lymphatic duct, which are a major cause of morbidity. To confirm the continued function of motor
nerves running through the lateral compartment (e.g., accessory or phrenic nerve), the
same neuromonitoring technique can be used
as for the recurrent laryngeal or vagal nerve. In
MTC, the dissection routinely includes level
II–V. In PTC without evidence of level I and II
involvement, the dissection may be restricted to
level III–V [173]. The sternocleidomastoid muscles are preserved unless they have been
invaded by thyroid cancer.
Mediastinal Compartment
Transsternal LND is warranted only for confirmed mediastinal nodes or extrathyroidal
extension of the primary cancer into the
infrabrachiocephalic mediastinum. A complete median sternotomy is required for full
exposure and complete removal of all fatty
tissue with the thymus and mediastinal
nodes down to the tracheal bifurcation and
the azygous vein. Special attention is paid to
183
LYMPH NODE DISSECTION IN THYROID CANCER
a
b
c
Fig. 13.2. Compartment-oriented microdissection of the central compartment [24] combined with total thyroidectomy. RLN,
recurrent laryngeal nerve; IONM, intraoperative neuromonitoring electrode; LTL, left thyroid lobe; RTL, right thyroid lobe; C1a, right
central neck compartment; C1b, left central neck compartment.
the course of the recurrent laryngeal nerve on
either side, which can be highly variable, and
to the mediastinal passage of the phrenic
nerve. Either nerve must be carefully preserved. When the central neck compartment
and the upper mediastinal compartment are
dissected in one session, they are removed
together as one contiguous surgical specimen
(Fig. 13.3).
Surgical Concept
Inadequate lymph node surgery is the main
cause of recurrent thyroid cancer [143]. It
more seriously affects those patients who initially present with gross rather than occult
disease [24, 41, 60]. Although there are no
good data regarding the impact of hospital or
surgeon expertise on outcome in thyroid cancer, it is reasonable to assume that professional
training and the experience of operating surgeons and their institutions decreases the rates
of tumor recurrence and surgical morbidity and
perhaps increases survival [174–178].
Typical of rare diseases such as thyroid
cancer, retrospective studies may be the sole
evidence base to derive treatment recommendations. When more than one treatment option
is available, the grade of each recommendation
must be considered. Unfortunately, retrospective studies are not well controlled most of the
time because there is often just one intervention or, when two or more interventions are
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ENDOCRINE SURGERY
Fig. 13.3. Transsternal four-compartment microdissection with combined microdissection of the central and mediastinal
compartment [24]. LTL, left thyroid lobe; RTL, right thyroid lobe; (C1a) right central neck compartment; (C1b) left central neck
compartment; (C2) right lateral neck compartment; (C3) left lateral neck compartment; (C4a) right upper mediastinal compartment;
(C4b) left upper mediastinal compartment; BCV, virtual level of the left brachiocephalic vein.
compared, assignment to treatment was not
randomized. As a consequence, unmeasured
and unmeasurable confounding factors cannot
be controlled for and may produce spurious
results and conclusions. The ‘‘best treatment’’
is selected based on ‘‘best available evidence’’
and the patient’s personal values and
preferences.
The following concept summarizes current evidence regarding surgical treatment
strategies (Table 13.3). This concept draws
on current literature, international practice
guidelines [6–8], and the authors’ experience with some 1500 patients with thyroid
cancer seen over a 13-year period at a single
institution, many of whom underwent reoperations for recurrence [179].
Papillary Carcinoma
When one weighs the considerable morbidity of LND (hypoparathyroidism, recurrent
laryngeal nerve palsy) against the low risk
of locoregional recurrence, there is no indication for routine LND for occult (10 mm)
node-negative PTC unless adverse features
are present, such as invasion of the thyroid
capsule, multifocal tumor growth, diffusesclerosing or tall cell variants, or distant
metastases. For all other PTC, compartment-oriented mircodissection (COMD) of
affected compartments is recommended.
Thereissomeevidencetosuggestthatroutine dissection of both lateral neck
compartments may be beneficial in highrisk PTC with special risk factors, such as
locally advanced or poorly differentiated
tumor growth, multiple central and lateral
node metastases ipsilateral to the primary
tumor, or the diffuse sclerosing variant.
For completion, all affected compartments
should be dissected in patients with multiple
node metastases who initially did not undergo
compartment-oriented microdissection and
now have locoregional recurrence. Single-node
recurrences do not necessitate extensive
reoperations.
Follicular Carcinoma
In FTC, node metastases are harbingers of systemic disease. Routine LND therefore is not a
key element of the surgical strategy. In nodepositive FTC with multiple node metastases, a
regional- or compartment-oriented approach is
favored over a focused approach or excision of
single nodes (‘‘berry picking’’). The key objective of lymph node surgery for FTC is local
control.
Medullary Thyroid Carcinoma
Stage is the single most powerful predictor of
outcome in MTC [114]. When stage is adjusted
for, there is no difference between sporadic and
hereditary MTC. Both forms of MTC are treated
equally, especially node-positive tumors. Subtle
differences in treatment may exist, for instance
185
LYMPH NODE DISSECTION IN THYROID CANCER
Table 13.3. Surgical concept of lymph node surgery in thyroid cancer
Tumor type Extent of disease Surgical strategy
PTC at first surgery:
– occult PTC (<10 mm), solitary, N0, M0, T1
– all other PTC
– node-positive PTC with special risk factors (e.g., T1-3b,
T4, diffuse sclerosing, tall cell, poor differentiation)
at reoperation:
– solitary LNM
– multiple LNM
FTC at first surgery:
– minimally or widely invasive FTC,
no LNM
– solitary LNM
– multiple LNM
no routine LND
routine COMD C1 and COMD of affected
compartment(s)
COMD C1–3
focused or regional LND
COMD
no routine LND
regional LND
COMD of affected compartment(s)
at reoperation:
– solitary LNM
– multiple LNM
focused or regional LND
regional LND or COMD of involved
compartment(s)
MTC at first surgery:
gene carriers, bCT $, sCT $
bCT $, sCT "
bCT "
no LND
COMD C1
COMD C1 – 3
noncarriers,
<5 mm, or sCT < 500 pg/ml
>5 mm, or sCT > 500 pg/ml
solitary or multiple LNM
COMD C1
COMD C1–3
COMD C1–3
at reoperation:
– solitary LNM
– multiple LNM
TNM, classification to TNM supplement, third edition [28];
COMD, compartment-oriented microdissection;
C1, central neck compartment according to the compartment classification [24], comprising levels I and VI of the classification of
American Academy of Otolaryngology, Head and Neck Surgery [27];
C1–3, central and both lateral neck compartments according to the compartment classification [24], comprising levels I–VI according to the
classification of American Academy of Otolaryngology, Head and Neck Surgery [27];
LND, lymph node dissection;
LNM, lymph node metastases;
bCT, basal calcitonin;
sCT, stimulated (peak) calcitonin;
$ normal serum levels
" elevated serum levels
COMD C1–3
COMD C1–3
in the early phase of MTC because occult hereditary MTC, unlike sporadic MTC, arises from
neoplastic C-cell hyperplasia. Basal and stimulated calcitonin levels were shown to differ
between node-negative and node-positive hereditary (but not in sporadic, occult MTC), more
than age or type of the respective germline
mutation [180]. The risk of node metastases
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is almost nonexistent in gene carriers with
normal basal calcitonin levels but increases
significantly when these levels are above normal [125–128, 181, 182]. For personalized
prophylactic surgery, the gene carrier’s age,
type of mutation [65, 131], and basal calcitonin levels are helpful when considering the
need for additional node dissection during
total thyroidectomy. In hereditary and sporadic MTC alike, the risk of node metastases
increases with primary tumors >5 cm [183]
and stimulated calcitonin values >500 pg/ml
[180]. In this setting, routine dissection of the
central and both lateralneckcompartmentsis
advised.
When MTC patients develop locoregional
recurrence in the neck after a less than compartment-oriented microdissection, the central and
both lateral neck compartments should be dissected for completion altogether. Conversely,
focused or regional approaches are usually adequate for recurrent MTC after previous compartment-oriented microdissection. The prognosis of patients with recurrent MTC obviously
hinges more on calcitonin-doubling times
[112] and CEA levels [113] than on initial
tumor stage. Unless they are high, elevated
calcitonin and CEA levels are compatible with
excellent long-term survival. In patients with
hypercalcitoninemia, new imaging techniques,
especially PET and contrast-enhanced CT and
MRI, localize previously ‘‘ oc cul t’’ dis eas e m ore
precisely than ever before. These advancements in imaging have enabled one to better
differentiate between patients with solely local
disease, which is amenable to surgery, and systemic disease.
Conclusion
Frequently, extension of the primary tumor
through the thyroid capsule and lymph node
metastases are early events in thyroid cancer,
especially with PTC and MTC. Regardless of
the effect on survival, lymph node metastases
are a frequent source of locoregional recurrence, which is often caused by an inadequate
initial operation. Lymph node metastases in
the neck and mediastinum are associated
with additional morbidity, from both the
tumor and the surgical efforts required to
remove it. Early detection and compartmentoriented microdissection hold the keys to
cure in thyroid cancer, calling for more professional training in the indications for, and the
extent and technique of, compartment-oriented
microdissection.
Metastatic thyroid cancers do not follow
the path of classic head and neck cancers. As a
corollary, a classification of locoregional nodes
originally devised for head and neck cancer cannot simply be translated to thyroid cancer by
analogy. Tailored to the locoregional lymph
node system of the thyroid, the compartment
classification is more suitable for thyroid cancer surgery and is the only system which
includes the infrabrachiocephalic upper mediastinal nodes.
Involvement of the lateral compartment of
the ipsilateral neck is almost as common as
central neck involvement, not just in PTC but
also in MTC. From an oncological point of
view, dissection of the central neck compartment alone is more diagnostic than therapeutic. Central LND may be adequate for early
thyroid cancer with a few positive nodes. For
previously untreated tumors with multiple
node metastases, the central neck compartment and the lateral neck compartment ipsilateral to the primary tumor are dissected as a
minimum. Although routine dissection of both
lateral neck compartments for node-positive
MTC is widely accepted, its use is more controversial in PTC unless these compartments
are clinically affected.
With the introduction of the revolutionary
concept of DNA-based prophylactic thyroidectomy [184, 185], it has become apparent
that node metastases in hereditary MTC cannot be reliably predicted by the gene carrier’s age or type of mutation. To minimize
both overtreatment and undertreatment of
carriers, basal calcitonin levels should be
determined. Normal basal levels suggest the
adequacy of total thyroidectomy alone,
unless there is clinical evidence to the contrary, whereas elevated basal levels indicate a
need for additional LND.
For palliation of thyroid cancer, the role of
lymph node surgery within a multidisciplinary
effort is limited. In locally advanced thyroid
cancer, LND can be effective in reaching local
control in the neck, silencing the ‘‘pacemaker of
the disease.’’
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LYMPH NODE DISSECTION IN THYROID CANCER
In conclusion, surgeons are the champions of
local control of thyroid cancer. Commanding an
armamentarium of highly sensitive and effective tools, they tailor the extent of surgery to
the extent of disease. Through the timely delivery of adequate initial operations, surgeons can
reduce the number of reoperations for recurrent
thyroid cancer, preventing unnecessary morbidity from local tumor invasion and corrective
surgical procedures.
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