1. Should we routinely perform prophylactic central neck dissection for patients with Papillary Carcinoma of the Thyroid?
Clarence Mak
NDH/AHNH

2. -Single 2cm right lobe thyroid nodule -LN -ve
30 year old
Female
No FHx of Thyroid Ca
USG
-Single 2cm right lobe thyroid nodule
-LN -ve
A malignant thyroid nodule tends to have ill-defined margins on ultrasound (Fig. 1). A peripheral halo of decreased echogenicity is seen around hypoechoic and isoechoic nodules and is caused by either the capsule of the nodule or compressed thyroid tissue and vessels [31]. The absence of a halo has a specificity of 77% and sensitivity of 67% in predicting malignancy [32].
Calcification
Fine punctate calcification (Fig. 2) due to calcified psammoma bodies within the nodule is seen in papillary carcinoma in 25%–40% of cases [16]. If used as the sole predictive sign of malignancy, microcalcification is the most reliable one with an accuracy of 76%, specificity of 93% and a positive predictive value of 70% [30]. Coarse, dysmorphic or curvilinear calcifications commonly indicate benignity (Fig. 3).
FNAC Psamomma body

3. Questions to ask
1. What is the rationale supporting routine prophylactic central neck dissection?
2. What are the arguments against prophylactic central neck dissection?
3. Current evidence ?

4. What is the rationale supporting routine central neck dissection?

5. 1. High incidence of microscopic disease
Incidence of clinically non-palpable (microscopic) disease more common than expected, 40-70%
Pre-op imaging not sensitive enough
USG
high specificity & PPV
low sensitivity in detecting cervical LN metastasis only 40-83%*
low negative predictive value (~60%) for central neck LN
Role of central compartment neck dissection for adequate assessment of nodal involvement/ guide staging . 
USG:
Preoperative ultrasonography have high specificity and positive predictive value, but low sensitivity (40 to 70%) and negative predictive value (of only about 61%) for the detection of lymph node metastases in the central neck compartment
Staging:
Authors report a 30% increase in the number of patients with T1 PTC (preoperatively considered to be N0), for whom 131I ablation was indicated following routine central and lateral nodal dissection demonstrating unexpected nodal metastases. The rational for this approach, in patients with tumors < 1 cm, is that positive lymph nodes are an indication for radioiodine ablation [10].
Stulak JM et.al Value of preoperative ultrasonography in the surgical management of initial and reoperative papillary thyroid cancer. Arch Surg 2006:141:5:

6. 2. LN metastasis and recurrence mainly in central neck
Central compartment is the most common site for LN metastases and recurrence
Recurrence is common
-up to 30% of patients
-up to 20 years after initial diagnosis
Mayo clinic 60-year observation for 900 patients
80% of recurrence located in central compartment
~1/4 will have recurrence, in central neck compartment
Roh JL et. al Total thyroidectomy plus neck dissection in differentiated thyroid carcinoma patients:pattern of nodal metastasis, morbidity, recurrence, and postoperative levels of serum parathyroid hormone. Ann Surg :
Hay ID et. al Papillary Thyroid microcarcionoma: a study of 900 cases observed in a 60-year period. Surgery :

7. 3. A guide for adjuvant radioactive iodine treatment
T1 tumours
Post surgical administriation of 131I depends on LN status
T1 tumour < 1cm, unifocal, N0
 131I not indicated
T1 PTC patients
Routine neck dissection identified a 30% increase in patients indicated for 131I ablation
preoperatively considered to be N0, found to have unexpected nodal metastases
Barczyński M, Konturek A, Stopa M, Nowak W: Prophylactic central neck dissection for papillary thyroid cancer. Br J Surg 2013, 100:410–418
Shindo M, Wu JC, Park EE, Tanzella F: The importance of central compartment elective lymph node excision in the staging and treatment of papillary thyroid cancer. Arch Otolaryngol Head Neck Surg 2006, 132:650–654

8. What are the arguments against prophylactic central neck dissection ?

9. Arguments AGAINST pCND
Most micrometastatic central LN are subclinical
 recurrences clinically significant?
Good prognosis of papillary Ca thyroid
10-year survival 95%, 15-year survival 90%
significant survival benefit?
Possibility of nerve injury and hypoparathyroidism
Very experienced surgeons
re-exploration of central compartment is still feasible, even if recurrence
 It has been reported that 38%–61% of patients are affected by PTC host lymph node micrometastases in the central compartment, yet only 7%–15% of them will develop clinically overt regional metastasis
 these data suggest that it is preferable that experienced surgeons perform therapeutic reoperation for central nodal metastasis on a small number of patients than for less-experienced surgeons to perform prophylactic CND in all patients
Low-volume centres less than 50 endocine operations annually
Micrometastatic  less than 2mm 9

10. What is the current evidence available?

11. Does it have increased risks?
Recurrent laryngeal nerve (RLN) injury
Hypoparathyroidism

12. Hypoparathyroidism -Transient -Permanent Hypoparathyroidism TT (%)
TT + CND
P-value
Study
-Transient 14 10 8 44 31 18
0.015
0.001
0.02
Roh,2007
Palestini, 2008
Sywak,2006
-Permanent
0.5 5
1.8
0.06
0.27
Roh, 2007
Earlier studies were mainly large case series or retrospective cohorts to look for differences in complication rates between two groups
Transient = less than 6 months
Transient Higher rate for TT + CND (statistically significant)
Permanent Higher rate for TT + CND (NOT statistically significant)

13. RLN injury -Transient -Permanent RLN injury TT (%) TT + CND P-value
Study
-Transient
4.1
1.3
1.0
7.3
5.4
1.8
0.39
0.06
0.62
Roh,2008
Roh, 2007
Sywak,2006
-Permanent
2.7
3.6
0.75
0.34
Palestini,2008
Palestini 2008 only ~300 people, 2 had permanent RLN injury (limited by rather small study, and the incidence of RLN by itself is very low, i.e. need a large population size to show a significant difference)
Transient/ Permanent  TT + CND with higher rates
NOT statistically significant

14. Meta-analysis Hypocalcaemia & RLN injury

15. Meta-analysis Hypocalcaemia & RLN injury
Relative risk
95% CI
Hypocalcaemia
Temporary
Permanent
2.52
1.82
RLN injury
Transient
1.44
1.14

16. Locoregional Control
Survival

17. -retrospective studies -short FU Meta-analyses -heterogenous studies
Previous evidence
-retrospective studies
-short FU
Meta-analyses
-heterogenous studies
-heterogenous results
PTC carries a good prognosis
Most studies with short FU unable to demonstrate a difference between TT/pCND vs TT

18. Retrospective cohort study, 10 years , 640 patients
282 TT ( ) vs 358 TT/pCND ( )
University Medical College in Krakow, Poland, between
Mostly TNM stage I patients (~56%) Included patients had PTC with NO evidence of nodal disease (based on preop P/E, imaging, no lymphadenopathy intraop)
Bilateral prophylactic CND
Locoregional recurrence = pathological evidence of disease on excision or cytology, or recurrent disease confirmed by 2 surveillance modalities (for example raised Tg concentration
and findings on whole body scan)

19. Result Total thyroidectomy 92.5% 87.6% Total thyroidectomy + pCND
Disease specific survival
Locoregional control rate
(No recurrence)
Total thyroidectomy
92.5%
87.6%
Total thyroidectomy + pCND
98.0%
94.5%
p= 0.034
p=0.003
Rationale for more patients receiving RAI was not an increase in availability, or more liberal use, but followed information concerning positive lymph nodes identified in 30.2% of surgical specimens following prophylactic CND, in which this was considered an indication for RAI therapy
thus CND upstaged many tumours that otherwise would not have been referred for adjuvant RAI treatment
recent studies have suggested that approximately 1/3 of patients who have prophylactic CND may be upstaged
Significant difference
More patients in the TT/pCND group received post op RAI therapy (64.5 vs 28%)
pCND guides proper RAI treatment, better prognosis

20. Included a more homogenous study population, (cN0 PTC)
11 studies with 2,318 patients
Included a more homogenous study population, (cN0 PTC)
Mean FU in months = 16 to 70 ( i.e. 1 year to 6 years)
One study with 10 years

21. Meta-analysis Results
Overall recurrence rate
TT (7.9%) vs TT/pCND (4.7%)
Relative risk of recurrence
0.59% (95% CI 0.33 – 1.07)
NNT in order to prevent a single recurrence = 31
Trend towards lower recurrence
failed to demonstrate statistical significance
(recurrence was mainly measured by serum Tg cervical USG/ WBS)

22. Current evidence Risk Benefit Temporary hypoparathyroidism
RLN injury risk same
Benefit
Trend of better survival and locoregional control
Not statistically significant in meta-analysis

23. Recommendations/ Guidelines

24. Recommendations Guidelines
Year
T1/T2
(tumour ≤4cm; not grown out of thyroid)
T3/T4
(Tumour >4cm or any tumour grown beyond thyroid
American Thyroid Association (ATA)
2009
Not recommended
Recommended
Japanese Society of Thyroid Surgeons
2011
French ENT Society
2012
British Thyroid Association
2014
Not recommended if:
-Age <45
-unifocal tumour
-no extrathyroidal extension
Personalized decision if:
-Age > 45
-multifocal tumour
-extrathyroidal extension

26. Burden from recurrence
30 year old, 2cm papillary carcinoma, LN –ve…...
Risk
Burden from recurrence
Survival

29. Recurrence
“Assuming a 7 year study with 5 years of follow-up, a 10% recurrence rate with 25% relative reduction as end-point…..
A total of 5840 patients required, to achieve at least 80% statistical power”
Morbidity
“Given the low rates of morbidity, several thousands of patients would need to be included to identify a significant difference in rates of permanent hypoparathyroidism and unintentional recurrent laryngeal nerve injury”
Carling T et al. American Thyroid Association design and feasibility of a prospective randomized controlled trial of prophylactic central lymph node dissection for papillary thyroid carcinoma. Thyroid 2012;3:237-44

30. Sentinel LN Biopsy

31. 114 patients with clinically node –ve PTC,
peri-tumoral injection of methylene blue intraop
All patients underwent TT + CND
SLN identified in 73.7% of patients
Results
-High specificity (100%) and PPV (100%)
-Sensitivity only 64.9% & false –ve rate 35.1%
suggesting that SLNB is not adequate as screening tool

32. Predictors of LN metastases

33. Presence of ≥ 2 factors related to survival:
An retrospective analysis of patients with PTC staged as pathological T1a
Subjects identified from (Surveillance, Epidemiology and End Results) cancer database from 1988 to 2007
Presence of ≥ 2 factors related to survival:
Male, African American, age ≥45, extra thyroidal extension, LN metastases, distant metastases
(Surveillance, Epidemiology and End Results) cancer database collects cancer incidence and survival data from 17 population based cancer registries, representing 26% of the US population

34. Other risk factors favoring recurrence:
-History of familial thyroid cancer
-Tumour factors
primary tumour > 2cm
multifocal
bilateral presence of disease in thyroid
The problem that remains is how to define the assessment criteria of high-risk patients, considering the fact that only the size of the tumor can be assessed preoperatively, while the type and the histological characteristics (that is locoregional infiltration and multifocality) can usually only be identified after surgery. We believe that a prophylactic central neck dissection should not be routinely recommended for smaller tumors (≤1 cm) while it may be advisable for larger tumors (>2 cm), especially if cytological suspicion of a high risk subtype arises or if there are intraoperative signs of extra-capsular spread.
A wider use of immunocytochemical and genetic markers could prove useful in better defining the high-risk population. For example, patients with RET/PTC oncogene expression have a higher rate of lymph node metastases [49], and this could constitute a useful factor to consider in the future. The development of techniques for the intraoperative identification of metastatic lymph nodes could also help the surgeon in this difficult choice.

35. BRAF mutation

36. BRAF mutation BRAF = B-type Raf kinase, located in chromosome 7
Most common mutation
conversion of valine to glutamate of amino acid, causing a constitutively active BRAF kinase
Active BRAF kinase being an oncogene in human cancer

37. 14 articles, 2470 patients from 9 different countries
Overall prevalence of BRAF mutation = 45%
Risk ratios of the following in BRAF mutation +ve patients:
-recurrence = 1.93 (95% CI, )
-LN metastasis = 1.71 (95% CI, )
-Advanced stage (AJCC III/IV) = 1.70 (95% CI, )
The ability of a biomarker (BRAF mutation) to confer a worse prognosis or a higher likelihood of recurrence/ persistence in the remnant thyroid bed, regional lymphatic nodes may help to effectively customize initial treatment to improve patient outcomes

38. Unilateral vs Bilateral neck dissection

39. Unilateral vs Bilateral
Unilateral pCND
-serves as an indicator of regional spread
-tool for selecting patients for further treatment
-lower morbidity rates than bilateral pCND
Unilateral pCNDsame rate of RLN injury, but lower rate of permanent hypoparathyroidism
Study with 1087 patients, from
Giordano D, Valcavi R, Thompson GB et al (2012) Complications of central neck dissection in patients with papillary thyroid carcinoma: results of a study on 1087 patients and review of the literature. Thyroid 22:911–917

40. Unilateral vs Bilateral
However,
central lymph node metastases (CLNM) can be found in 25% of contralateral level VI
Thus, unilateral PND may not be considered as a therapeutic step in patients with CLNM
Raffaelli M, De Crea C, Sessa L et al (2012) Prospective evaluation of total thyroidectomy versus ipsilateral versus bilateral
central neck dissection in patients with clinically node-negative papillary thyroid carcinoma. Surgery 152:957–964

41. Unilateral vs Bilateral
Moo and colleagues*
-116 patients with PTC
-Tumour ≤1cm 0 patients with +ve LN bilaterally
Tumour >1cm 31% with +ve LN bilaterally
Skip metastases in contralateral level VI present in 5-10% of patients, except for PTCs <10mm#
Tumours ≤1cm unilateral pCND
Tumours >1cmbilateral pCND
Just from level 4 evidencei.e. case series
Based on our experience, we believe that total thyroidectomy associated with prophylactic CND ipsilateral to the tumor, intraoperative frozen-section pathology, and completion contralateral paratracheal lymph node neck dissection in presence of lymph node metastasis may represent an effective strategy in the treatment of PTC with clinically negative neck lymph nodes
*Moo TA, Umunna B, Kato M, Butriago D, Kundel A, Lee JA et al. Ipsilateral versus bilateral central neck lymph node dissection in papillary thyroid carcinoma. Ann Surg 2009; 250: 403–408.
#Hartl DM, Leboulleux S, Al Ghuzlan A et al (2012) Optimization of staging of the neck with prophylactic central and lateral neck dissection for papillary thyroid carcinoma. Ann Surg 255:777–783

42. Post operative radioactive iodine ablation

43. Post-operative radioiodine ablation therapy
Radioactive iodine
-aims to destroy any possible occult residual microscopic thyroid carcinoma
to reduce future disease recurrence
Side effects
-Salivary dysfunction, nasolacrimal duct obstruction
-small risk of 2o primary malignancies

44. Post-op ablative radioiodine
Recent consensus:
Post surgical administriation of 131I
classified as T1 (diameter < 2cm)
depends on LN status

45. T1 tumour, < 1cm, unifocal, N0
 131I not indicated
T1, N1
 131I indicated
T1Nx & T1N0 but above 1cm
no consensus

46. Is prophylactic CND useful in finding the patients with T1N1, who were initially thought to be T1N0, in which 131I would now be indicated?

47. Literature reports a 30% increase in the number of patients with T1 PTC (preoperatively considered to be N0), for whom 131I ablation was indicated following routine neck dissection demonstrating unexpected nodal metastases.
Barczyński M, Konturek A, Stopa M, Nowak W: Prophylactic central neck dissection for papillary thyroid cancer. Br J Surg 2013, 100:410–418
Shindo M, Wu JC, Park EE, Tanzella F: The importance of central compartment elective lymph node excision in the staging and treatment of papillary thyroid cancer. Arch Otolaryngol Head Neck Surg 2006, 132:650–654

48. TNM staging
TNM classification does not differentiate between micro- or macro-metastatic lymph nodes and does not sub-classify lymph node disease between the lateral and central cervical compartments.

49. Levels of evidence

50. Anatomy Central neck compartment
Superior = hyoid bone
Laterally = carotid arteries
Anteriorly = superficial layer of the deep cervical fascia
Posteriorly = deep layer of the deep cervical fascia
Inferior = innominate artery on the right and the corresponding axial plane on the left
Carty et. al Consensus Statement on the Terminology and Classification of Central Neck Dissection for Thyroid Cancer. Thyroid 2009; vol 19, no. 11

51. Terminology Central neck dissection
Minimum
-prelaryngeal
-pretracheal
-at least one paratracheal basin
Extended
-retropharyngeal
-retroesophageal
-paralaryngopharyngeal
(superior to vascular pedicle)
-superior mediastinal
(inferior to innominate artery)

52. Possibility of high level evidence?

53. Terminology Therapeutic neck dissection
nodal metastasis apparent clinically (preoperatively/ intraoperatively) or by imaging (clinically N1a)
Prophylactic (elective) neck dissection
nodal metastasis was not detected clinically or by imaging (clinically N0)

54. Lateral neck LN dissection

55. Prophylactic Lateral Neck Dissection
Supporters
-Prophylactic lateral neck dissection can identify and better stage the >50% of patients with +ve central nodes who will have metastatic nodes in levels III/ IV
Against
-No evidence that prophylactic neck dissection improves survival or loco-regional control
-overtreats 75% of patients
BTA guidelines, 2014
No evidence of central compartment LN
prophylactic lateral neck dissection not recommended
Central compartment LN +ve
Personalized decision making

56. Therapeutic Lateral Neck Dissection
Patients with overt metastatic disease in lateral neck will have clinical/ radiological evidence of central neck LN metastases in more than 80% of cases
Suspicious/ clinically involved nodes in lateral neck
therapeutic central and selective lateral neck dissection (levels IIa-Vb) recommended
accessory nerve, SCM, and interal jugular vein preserved

57. CND reducing recurrence
950 patients with PTC, over a 15 year period
Neck dissection (75%)
84% only central compartment

58. CND reducing recurrence
Staging
I (46%), II (26%), III (22%), IV (7%)
Recurrence
LN dissection = 6.8%
No LN dissection = 16.5%
stage I (1%), stage II (5.7%), stage III (6.1%), stage IV (77.3%)
Toniato A et.al. Papillary thyroid carcinoma: factors influencing recurrence and survival. Ann Surg Oncol 2008;15:

59. 4. Lowers Tg level Lowers postoperative thyroglobulin levels
Undetectable thyroglobulin level
TT + CND (72%) vs TT (43%)
More effective detection of persistent/ recurrent disease
ATA recommended every months Tg assessment
Sywak M, Cornford L, Roach P, et al. Routine ipsilateral level VI lymphadenectomy reduces postoperative thyroglobulin levels in papillary thyroid cancer. Surgery 2006;140:1000-5; discussion