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Surgery for Metastatic Neck
Disease of Thyroid Cancer
Henning Dralle University of Halle, Germany [email protected]
Key Note Lecture 4, WCTC, Toronto, July 12, 2013
The art and clinical practice of
surgery for metastatic neck
disease of thyroid cancer
should be embedded in a
multidisciplinary team
approach and follow
clinical evidence
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clinical
endocrinology
nuclear
medicine
radiology
molecular imaging
medical
oncology
radio-
oncology
speech and
physiotherapy
psycho-
oncology
molecular
genetics
histopathology
immunohisto-
chemistry
The dilemma:
Current treatment guidelines are using various levels
of evidence and grades of recommendations that
sometimes may be difficult to understand concerning
final treatment decisions for both,
the doctor and the patient:
individualized thyroid cancer treatment
recommendations should offer treatment
corridors instead of more or less graded
two dimensional (yes or no) concepts
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NEJM 2010, 363: 1076 - 1079
Changing the current concept of treatment
recommendations from a two-dimensional
to a three-dimensional system:
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Pristipino et al. NEJM 2013; 369: 89 - 90
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ethical considerations
There are several
interactions in
between
prognostic relevance
surgical morbidity
Why preferring the three-instead of
two-dimensional concept for individualized
treatment recommendations in thyroid cancer?
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Ethical considerations
Surgery in contrast to most diagnostic procedures
destroys the anatomical physical integrity, and
creates intervention-related morbidity. Elective
thyroid cancer surgery therefore should reduce over-
and undertreatment to a minimum in order to reduce
surgical morbidity.
As more the intervention is including uncertainties
related to anticipation of disease development
("prophylactic") the patient's individual wishes and
goals have to be part of final decision concerning
planning and conduction of surgery.
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LNM are an indicator for increased risk of systemic
disease and locoregional recurrence. However, both
are dependent on tumor type, and at present there is
no biomarker available in TC (similar to other
malignancies) clearly differentiating between
locoregional only and systemic disease.
Based on tumor biology the concept of "prophylactic"
node dissection therefore is rather arbitrary and
limited by the detection limits of imaging techniques
for differentation of cN0 vs. cN1 and cM0 vs. cM1.
Prognostic relevance
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Prognostic impact of N staging
in PTC and MTC
Significant differences
for
• 1 – 5, 6 – 10, 11 – 20 LNM
• > 20 LNM
Significant differences
for
• 1 – 10 LNM
• > 10 LNM
Machens and Dralle, JCEM 2012; 97: 4375 – 4382 Machens and Dralle, Ann Surg 2013; 257: 323 - 329
PTC MTC
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With decreasing risk of locoregional and systemic disease
surgical morbidity related to "prophylactic" maneuvers are
of increasing importance.
There are several specific potential complications related
to central (RLN palsy, hypoparathyroidism) and lateral
neck surgery (injury of the spinal, vagus, and phrenic
nerve, sympathic trunc, thoracic duct) which are well
known, however, rarely studied systematically and in a
prospective way. In particular, permanent hypopara is ill-
defined, and there is no consensus about surgical and
metabolic risk factors.
Surgical morbidity
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Based on the characteristics of the various types of
thyroid cancer, and the present knowledge about
disease- and treatment-related risk factors the
three-dimensional concept better defines the corridor
for individualized decisions than the current practice
seeking for a single threshold for intervention.
The three-dimensional concept
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Anatomic and oncologic
boundaries of the
locoregional system
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Oncologic
Locoregional lymph nodes and
metastases not associated with
distant disease
Anatomic The central, lateral, and upper
mediastinal compartment
The locoregional space in thyroid cancer
by oncologic and anatomic definition
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The central lymph node compartment
Superior: hyoid bone
Lateral: common carotid artery
Anterior: fascia posterior to SSM
Posterior: prevertebral fascia
Inferior: BCV; origin of RIA/LCCA
Ill defined:
• parapharyngeal nodes
• level 7 (between ITA, RIA/LCCA, and
BCV)
• thyrothymic ligament
Of note:
The clinical "anterior superior mediastinum"
anatomically is the inferior neck
Carty et al., Thyroid 2009; 19: 1153 - 1158 16/47 HD
Right parapharyngeal LNM LNM at level 7
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The lateral lymph node compartment
Level 1: submandibular, submental
Level 2: upper jugular
Level 3: mid jugular
Level 4: lower jugular
Level 5: posterior triangle
Ill defined:
• superior borders of L2
• lateral borders of L5
Stack et al., Thyroid 2012; 22: 501 – 508
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The mediastinal lymph node compartment
LTL RTL
level of
brachiocephalic
left vein
Dralle et al., Surg Today 1994; 24: 112 - 121 19/47 HD
Main aims of surgery for locoregional LNM of thyroid cancer
are local tumor control by
• radical removal of symptomatic or asymptomatic node
metastasis, in particular with imminent or already manifest
invasion of vital structures
• local palliation (symptomatic met)
Unproven:
• oncologic benefit of locoregional staging ("prophylactic
LND")
• prevention of distant met ("metastasis of metastasis")
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LND
in PTC
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Locoregional LND in PTC Controversial issues
"Prophylactic"
• central
• lateral
Therapeutic
• central
• lateral
• mediastinal
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"Prophylactic"
central or lateral LND in PTC
The term "prophylactic" reflects a
compromise concerning the limited value
of preop imaging in detecting LNM
rather than the belief that the
removal of uninvolved LN
is of any oncologic benefit.
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Routine CND in PTC
• most studies agree that routine CND does not improve CSS (Moreno 2012; Shan 2012; a. o.)
• RCND may decrease locoregional rate of recurrence, but does not
increase morbidity due to redo surgery in experienced hands (Hartl 2013; a.o.)
• preop imaging (US or CT or both) or even BRAF is not sensitive
enough for individualizing CND (Moreno 2012; Lee 2013; a.o.)
• When compared with final histopathology accuracy of FS was about
90 %, however, the method for selecting LN to FS is still unclear (Lim 2012)
• Morbidity concerning postop permanent hypopara in contrast to
permanent RLNP is increased after bilateral but not after unilateral CND (Giordano 2012)
cN0
FS -
Primary tumor size > 10 mm,
extracapsular invasion,
BRAF +
cN1
FS +
No Risk factors in favor of → Yes
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Routine lateral ND in PTC
• Along with the ATA guidelines (2009) most studies agree that
prophylactic lateral ND does not improve survival. Considering
potential morbidity related to lateral nerves and the thoracic duct
prophylactic lateral ND therefore is not recommended (ATA, R27a and 28)
• However, there are some risk factors associated with an increased
frequency of lateral LNM:
- more than 5 LNM in the central compartment (Machens 2009)
- LNM in level 7 (Lee 2009)
- primaries in the upper pole of the thyroid skipping the central
compartment (Park 2012; Zhang 2012)
- multifocal, bilateral, and extrathyroidal invasion (Zhang 2012)
cN0 upper pole primaries, L7 +,
> 5 CLNM, multifocal, extrathyr. cN1
No Risk factors in favor of → Yes
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Level 7 ND in a patient
with lateral node-positive (5/19) PTC
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Level 7 ND in a patient
with lateral node-positive (5/19) PTC
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Skip metastases to the lateral
compartment in upper pole primaries
20 – 30 % of upper pole
primaries compared to
10 – 20 % in middle and
lower pole primaries (Park 2012)
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With few exceptions (patient related; small LNM) surgery
is the preferred treatment modality for initial or recurrent
lymph node metastases in the neck.
Most surgeons agree that the technique for LND in
most cases at least in primary surgery should be
compartmental instead of focussed to single nodes.
Accuracy of imaging and FNAC/TG washout is better for
the lateral compared to the central compartment
Therapeutic LND in PTC
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However,
there are several areas of uncertainty concerning the
extent of node dissection:
central compartment
- uni- or bilateral?
- including thyrothymic ligament?
- including Delphi- and level 7 nodes?
lateral compartment
- including para/retropharyngeal, level 1, 2B, 5A?
Therapeutic LND in PTC
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Therapeutic CND in PTC Areas of uncertainty
• The risk for postop hypopara is significantly higher with than w/o
cervical thymectomy (El Khatib 2010) and after bilateral than unilateral
level 6 dissection (Giordano 2012)
Routine bilateral CND?
• The risk for level 7 LNM is positively correlated with primary tumor size
and the number of level 6 LNM (Lee 2009)
Routine level 7 dissection?
• Delphian LNM are observed in about 10 % - 20 % PTC (Kim 2012, Gopalakrishna
2011, Isaacs 2008), they are representing an adverse prognostic sign (higher
LN ratio, lateral comp. involvement, higher rates of ETE).
Routine Delphian LN removal?
BCND few unilateral LNM thyroid bilateral multifocal bilateral or extensive
unilateral LNM
L7 few L6 LNM lateral LNM cN1
DND unsuspicious DN upper pole primaries cN1
No Risk factors in favor of → Yes
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Pattern of spread to the lateral neck in PTC
Results of a metaanalysis
Level Metastatic involvement (%)
2a 53
2b 16
3 71
4 66
5a 8
5b 22
18 studies with 1145 patients and 1298 neck dissections included
Eskander et al., Thyroid 2013; 583 – 592
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Therapeutic LND in PTC Areas of uncertainty
L1/2 cN0 capsular invasion;
high LN ratio-, multilevel,
in particular L3/L4 LNM
cN1
L5 cN0 cN1
No Risk factors in favor of → Yes
Only about 20 % of lateral LNM are occurring in levels 1, 2 and 5 (Robenshtok
2012), however, causing the majority of complications with various nerve
injuries (accessory, marginal mandibular, hypoglossal, greater auricular) (10
– 30 %), and chyle leak (3 – 8 %) (Stack 2012).
Risk factors for occult LNM in level 2 were level 3 and 4 met, or > 4 LNM (Koo 2010)
Routine level 2 ND in patients with node-positive lateral neck?
Risk factors for occult LNM in level 5 were capsular invasion, multilevel and
in particular level 3 and 4 LNM (Lim 2010; Shim 2013)
Routine level 5 ND in patients with node-positive lateral neck?
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Mediastinal LNM have been
shown to carry only a
moderte risk of lung
metastases compared to a
high ratio of LNM in the
neck (Machens 2012).
In contrast to MTC
therapeutic mediastinal ND
in PTC is reasonable and
may be the preferred
option in radioiodine-
refractory disease without
distant met.
Therapeutic mediastinal LND in PTC
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Lymph node dissection in PTC Summary
Routine central cN0
FS -
prim tumor size > 10 mm;
ETE; BRAF positiv
cN1
FS +
lateral cN0
upper pole primaries;
positive L7; > 5 LNM;
multifocal; ETE
cN1
Therapeutic
central
BCND few unilat.
LNM
bilateral thyroid
primaries
bilateral or extensive
unilat. LNM
L7 few L6 LNM lateral LNM cN1
DND unsuspicious
DN upper pole primaries cN1
lateral L1/2
cN0
ETE; high LN ratio;
multilevel, in particular
L3/L4 LNM
cN1 L5
mediastinal progressive
distant met indivdual
Radioiodine-
refractory LNM
without DM
No Risk factors in favor of → Yes
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LND
in MTC
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Due to its metabolic differences to TC there is no option for RI treatment of
metastatic MTC. Nodal met drastically reduce the chance for cure, however,
the reason for biochemical non-cure is not always occult distant disease.
This observation is the rationale behind the concept of compartment-oriented
microdissection initiated by Lars Tisell in 1986.
On the other hand, occult (systemic) disease often is associated with
acceptable long-term outcome (van Heerden 1990). However, at the time of first
surgery there are no biomarkers routinely available (like BRAF in PTC) for
stratifying the extent of surgery, only stage my be of some prognostic value.
Last, but not least, patients with persistent hypercalcitonemia are often
considerable warried about the prognostic impact of increased calcitonin
levels.
Locoregional LND in MTC Background of controversies
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Locoregional LND in MTC with curative intent,
controversial issues between
under- and overtreatment
Routine ND in occult/early sporadic and hereditary MTC
Routine lateral ND in clinical MTC
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Biochemical cure after TT plus ND for
occult/early sporadic and hereditary MTC
pT (mm) N1 (%) BC (%)
< 2 spor (15)
her (51)
13
6
85
96
3 – 4 spor (15)
her (29)
20
14
69
80
5 – 6 spor (26)
her (26)
23
42
88
79
7 – 8 spor (28)
her (13)
36
62
62
62
9 – 10 spor (23)
her (7)
43
43
77
71
n = 233; 201 with CND; 127 with CND and LND
Machens and Dralle, JCEM 2012; 97: 1547 - 1553
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Basal calcitonin, largest primary tumor
diameter, LNM, and biochemical cure in
sporadic and hereditary MTC
Basal calcitonin
(< 10 pg/ml)
n Largest pT
(mm)
N1
(%)
Biochemical cure
(%)
10 – 20 23 3.3 (2.4; 4.2) 0 100
20 – 50 35 4.5 (3.5; 5.4) 11 100
50 – 100 23 6.2 (4.5; 7.8) 17 100
100 – 200 26 8.9 (6.7; 11.0) 35 81
200 – 500 29 11.4 (9.7; 13.0) 45 81
500 – 1000 34 20.4 (15.0; 25.9) 59 50
1000 – 2000 34 24.0 (19.2; 28.8) 53 40
2000 – 10000 39 27.5 (23.3; 31.7) 79 18
> 10000 25 34.9 (28.3; 41.6) 96 0
300 consecutive previously untreated MTC
Machens and Dralle, JCEM 2010; 95: 2655 - 2663 40/47 HD
Basal calcitonin and lymph node status
in sporadic and hereditary MTC
Basal calcitonin
(< 10 pg/ml) n
pN1
(%)
Compartments involved in pN1 MTC (%)
Ipsilateral Contralateral Mediastinal DM
centr lat centr lat
10 – 20 23 0 0 0 0 0 0 0
20 – 50 35 11 75 75 0 0 0 0
50 – 100 23 17 50 75 25 0 0 0
100 – 200 26 35 78 44 11 0 0 0
200 – 500 29 45 77 85 23 31 0 0
500 – 1000 34 59 80 85 35 20 20 6
1000 – 2000 34 53 72 78 45 55 22 15
2000 – 10000 39 79 87 94 45 55 13 15
> 10000 25 96 83 96 76 83 54 72
300 consecutive previously untreated MTC
Machens and Dralle, JCEM 2010; 95: 2655 - 2663 41/47 HD
MicroMTC < 2 mm has the highest chance to be cured (90 %) by surgery, but
US in contract to basal Ct is not valid at this stage
MTC with basal Ct < 20 corresponding to pT of about 3 mm had no LNM,
therefore need no LND
MTC with basal Ct of 20 – 50 pg/ml, corresponding to pT of 3 – 5 mm, had
ipsilateral central and lateral LNM in about 10 %
MTC with basal Ct of 50 – 200 pg/ml, corresponding to pT of 5 – 10 mm, had
central (ipsi- and contralat) and ipsilat lateral LNM in about 10 – 35 %
MTC with basal Ct of > 200 pg/ml, corresponding to pT > 10 mm, had bilateral
central and bilateral lateral LNM in > 45 %
Central and lateral ND for curative intent
in sporadic und hereditary MTC
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Surgical options for LND in sporadic and
hereditary MTC according to preop basal Ct
and primary tumor size
Basal Ct (< 10 pg/ml)
Tumor size (mm)
< 20
< 3
20 – 50
3 – 5
50 – 200
5 – 10
> 200
> 10
Option 1 TT ICND + ILND BCND + ILDN BCND + BLND
Option 2 TT
ICND,
staged ILND
BCND,
staged ILND
BCND + ILND,
staged CLND
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Benefit-risk balance for contralateral compartment
dissection at first MTC surgery in partients with
Ct > 200 pg/ml and unsuspicious LN
• increased morbidity (L > R)
• unproven survival benefit
because contralateral microMet
often part of occult systemic
disease
• overtreatment for those w/o
contralateral LNM
• optimum locoregional staging
incl. risk assessment for
systemic disease
• psychological advantage
(complete neck clearance;
postop increased Ct exclude
persistent locoregional disease)
• avoidance of redo for
metachronous contralateral
LNM
• informed consent after detailed information about pros & cons
• preference in favor of CLCD for bilateral and left lobe MTC
• staged CLCD for right lobe MTC with metachronous contralateral LNM
CONS PROS
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FTC und UTC do not require any type of routine LND
Due to the limited level of evidence recommendations for
LND in PTC and MTC should offer a treatment corridor to
the patient, but not only "yes" or "no" strategies
Lymph node dissection in thyroid cancer
Take home (1)
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Bilateral CND also in experienced hands is associated with an increased risk
for permanent hypopara, contralateral CND should be reserved for patients
with increased risk of nodal involvement
CND is overrepresented in the current literature compared to lateral ND which
may be more difficult and more risky. At the same time CND is only partly
standardized, some technical aspects including the minimum number for LN
retrieval should be defined more precisely
Lateral node dissection bears significant risk for QOL affecting
complications, and should be performed in PTC preferentially with
therapeutic intent and limited to the involved levels
Lymph node dissection in thyroid cancer
Take home (1)
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Basal calcitonin level should be added but not replaced
by ultrasound in guiding LN surgery for MTC
Primary MTC < 3 mm with basal Ct levels < 20 pg/ml do
not require LND
In primary MTC > 3 mm with basal Ct levels > 2o pg/ml
staged ipsilateral (Ct < 50) or bilateral (> 200) ND may be
an alternative option to initial lateral ND
Lymph node dissection in thyroid cancer
Take home (2)
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