Should we routinely perform Should we routinely perform prophylactic central neck prophylactic central neck

dissection for patients with dissection for patients with Papillary Carcinoma of the Papillary Carcinoma of the

Thyroid?Thyroid?

Clarence MakClarence Mak NDH/AHNHNDH/AHNH

30 year old30 year old FemaleFemale No FHx of Thyroid No FHx of Thyroid

CaCa USGUSG

-Single 2cm right -Single 2cm right lobe thyroid nodulelobe thyroid nodule-LN -ve-LN -ve

Questions to askQuestions to ask

1. What is the rationale supporting 1. What is the rationale supporting routine prophylactic central neck routine prophylactic central neck dissection?dissection?

2. What are the arguments against 2. What are the arguments against prophylactic central neck prophylactic central neck dissection?dissection?

3. Current evidence ?3. Current evidence ?

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

1. High incidence of microscopic 1. High incidence of microscopic diseasedisease

Incidence of clinically non-palpable Incidence of clinically non-palpable (microscopic) (microscopic) disease more common than expected, 40-70% disease more common than expected, 40-70%

Pre-op imaging Pre-op imaging not sensitivenot sensitive enough enough

USG USG high specificity & PPVhigh specificity & PPV

low sensitivity low sensitivity in detecting cervical LN metastasis only 40-83%*in detecting cervical LN metastasis only 40-83%*low negative predictive value low negative predictive value (~60%) for central neck LN(~60%) for central neck LN

Role of central compartment neck dissection for Role of central compartment neck dissection for adequate assessment of adequate assessment of nodal involvement/ guide nodal involvement/ guide stagingstaging

Stulak JM et.al Value of preoperative ultrasonography in the surgical management of initial and reoperative papillary thyroid cancer. Arch Surg 2006:141:5:489-494

2. LN metastasis and 2. LN metastasis and recurrence mainly in central recurrence mainly in central neckneck

Central compartment is the most common site for Central compartment is the most common site for LN LN metastasesmetastases and and recurrencerecurrence

Recurrence is commonRecurrence is common-up to 30% of patients-up to 30% of patients-up to 20 years after initial diagnosis-up to 20 years after initial diagnosis

Mayo clinic 60-year observation for 900 patientsMayo clinic 60-year observation for 900 patients80% of recurrence located in central compartment 80% of recurrence located in central compartment

~1/4 will have recurrence, in central neck 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 2007 245:604-610

Hay ID et. al Papillary Thyroid microcarcionoma: a study of 900 cases observed in a 60-year period. Surgery 2009.144: 980-987

3. A guide for adjuvant 3. A guide for adjuvant radioactive iodine treatmentradioactive iodine treatment

T1 tumoursT1 tumoursPost surgical administriation of Post surgical administriation of 131131I depends on I depends on LN status

T1 tumour < 1cm, unifocal, N0T1 tumour < 1cm, unifocal, N0 131131I not indicated I not indicated

T1 PTC patientsT1 PTC patients Routine neck dissection identified a 30% increase in Routine neck dissection identified a 30% increase in

patients indicated for patients indicated for 131131I ablationI ablation preoperatively considered to be N0, found to preoperatively considered to be N0, found to have have unexpected nodal metastases 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

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

Arguments AGAINST pCNDArguments AGAINST pCND

Most micrometastatic central LN are subclinical Most micrometastatic central LN are subclinical recurrences clinically significant?recurrences clinically significant?

Good prognosis of papillary Ca thyroidGood prognosis of papillary Ca thyroid 10-year survival 95%, 15-year survival 90%10-year survival 95%, 15-year survival 90%

significant survival benefit?significant survival benefit?

Possibility of Possibility of nerve injurynerve injury and and hypoparathyroidism hypoparathyroidism

Very experienced surgeonsVery experienced surgeons re-exploration of central compartment is still feasible, even if re-exploration of central compartment is still feasible, even if

recurrence recurrence

What is the current What is the current evidence available?evidence available?

Does it have increased Does it have increased risks?risks?

Recurrent laryngeal nerve (RLN) Recurrent laryngeal nerve (RLN) injuryinjury

HypoparathyroidismHypoparathyroidism

HypoparathyroidismHypoparathyroidism

HypoparathyroidiHypoparathyroidismsm

TTTT

(%)(%)TT + TT + CNDCND

(%)(%)

P-P-valuvalu

ee

StudyStudy

--TransientTransient1414

1010

88

4444

3131

1818

0.0150.015

0.0010.001

0.020.02

Roh,2007Roh,2007

Palestini, Palestini, 20082008

Sywak,2006Sywak,2006

--PermanentPermanent00

0.50.555

1.81.80.060.06

0.270.27Roh, 2007Roh, 2007

Sywak,2006Sywak,2006

Transient Higher rate for TT + CND (statistically significant)

Permanent Higher rate for TT + CND (NOT statistically significant)

RLN injury RLN injury

RLN injuryRLN injury TTTT

(%)(%)TT + TT + CNDCND

(%)(%)

P-P-valuevalue

StudyStudy

--TransientTransient4.14.1

1.31.3

1.01.0

7.37.3

5.45.4

1.81.8

0.390.39

0.060.06

0.620.62

Roh,2008Roh,2008

Roh, 2007Roh, 2007

Sywak,2006Sywak,2006

--PermanentPermanent2.72.7

003.63.6

1.31.30.750.75

0.340.34Roh, 2007Roh, 2007

Palestini,20Palestini,200808

Transient/ Permanent TT + CND with higher rates

NOT statistically significant

Meta-analysisMeta-analysisHypocalcaemia & RLN injuryHypocalcaemia & RLN injury

Meta-analysisMeta-analysisHypocalcaemia & RLN injuryHypocalcaemia & RLN injury

Relative riskRelative risk 95% CI95% CI

HypocalcaemiaHypocalcaemia TemporaryTemporary

PermanentPermanent2.522.52

1.821.821.95-3.251.95-3.25

0.51-6.50.51-6.5

RLN injuryRLN injury TransientTransient

PermanentPermanent1.441.44

1.141.140.59-3.550.59-3.55

0.46-2.830.46-2.83

Locoregional Locoregional Control Control

Survival

Previous evidence Previous evidence -retrospective studies-retrospective studies-short FU-short FU

Meta-analysesMeta-analyses-heterogenous studies-heterogenous studies-heterogenous results-heterogenous results

PTC carries a good prognosisPTC carries a good prognosisMost studies with short FU unable to demonstrate a Most studies with short FU unable to demonstrate a difference between TT/pCND vs TTdifference between TT/pCND vs TT

Retrospective cohort study, Retrospective cohort study, 10 years10 years , 640 , 640 patientspatients

282 TT (1993-1997) vs 358 TT/pCND (1998-2002)282 TT (1993-1997) vs 358 TT/pCND (1998-2002)

ResultResultDisease Disease specific specific survivalsurvival

Locoregional Locoregional control ratecontrol rate(No recurrence)(No recurrence)

Total Total thyroidectomythyroidectomy

92.5%92.5% 87.6%87.6%

Total Total thyroidectomy + thyroidectomy +

pCNDpCND

98.0%98.0% 94.5%94.5%

p= 0.034p= 0.034 p=0.003p=0.003•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

11 studies with 2,318 patients 11 studies with 2,318 patients

Included a more homogenous study population, (cN0 PTC)Included a more homogenous study population, (cN0 PTC)

Meta-analysisMeta-analysisResultsResults

Overall recurrence rateOverall recurrence rateTT (7.9%) vs TT/pCND (4.7%)TT (7.9%) vs TT/pCND (4.7%)

Relative risk of recurrenceRelative risk of recurrence0.59% (95% CI 0.33 0.59% (95% CI 0.33 –– 1.07) 1.07)

NNT in order to prevent a single recurrence = NNT in order to prevent a single recurrence = 31 31

Trend towards lower recurrenceTrend towards lower recurrencefailed to demonstrate statistical significancefailed to demonstrate statistical significance

Current evidenceCurrent evidence

RiskRiskTemporary hypoparathyroidism Temporary hypoparathyroidism

RLN injury risk sameRLN injury risk same

BenefitBenefitTrend of better survival and locoregional Trend of better survival and locoregional

controlcontrol Not statistically significant in meta-analysis Not statistically significant in meta-analysis

Recommendations/ Recommendations/ GuidelinesGuidelines

RecommendationsRecommendationsGuidelinesGuidelines

YearYear T1/T2 T1/T2 (tumour (tumour ≤≤4cm; 4cm; not grown out of not grown out of thyroid)thyroid)

T3/T4T3/T4(Tumour >4cm or (Tumour >4cm or any tumour grown any tumour grown beyond thyroidbeyond thyroid

American Thyroid Association American Thyroid Association (ATA)(ATA)

20092009 Not recommendedNot recommended RecommendedRecommended

Japanese Society of Thyroid Japanese Society of Thyroid SurgeonsSurgeons

20112011 RecommendedRecommended RecommendedRecommended

French ENT SocietyFrench ENT Society 20122012 RecommendedRecommended RecommendedRecommended

British Thyroid AssociationBritish Thyroid Association 20142014 Not recommended if:Not recommended if:

-Age <45-Age <45

-unifocal tumour-unifocal tumour

-no extrathyroidal -no extrathyroidal extension extension

Personalized decision if:Personalized decision if:

-Age > 45 -Age > 45

-multifocal tumour-multifocal tumour

-extrathyroidal extension-extrathyroidal extension

Risk

Survival Burden from recurrence

30 year old, 2cm papillary carcinoma, LN –ve…...

RecurrenceRecurrence ““Assuming a 7 year study with 5 years of follow-up, a 10% recurrence rate Assuming a 7 year study with 5 years of follow-up, a 10% recurrence rate

with 25% relative reduction as end-pointwith 25% relative reduction as end-point…….... A total of A total of 5840 patients5840 patients required, to achieve at least 80% statistical power required, to achieve at least 80% statistical power””

MorbidityMorbidity ““Given the low rates of morbidity, Given the low rates of morbidity, several thousandsseveral thousands of patients would of patients would

need to be included to identify a significant difference in rates of need to be included to identify a significant difference in rates of permanent hypoparathyroidism and unintentional recurrent laryngeal permanent hypoparathyroidism and unintentional recurrent laryngeal nerve injurynerve injury””

Sentinel LN BiopsySentinel LN Biopsy

114 patients with clinically node –ve PTC, 114 patients with clinically node –ve PTC,

peri-tumoral injection of methylene blue peri-tumoral injection of methylene blue intraopintraop

All patients underwent TT + CNDAll patients underwent TT + CND SLN identified in 73.7% of patientsSLN identified in 73.7% of patients ResultsResults

-High specificity (100%) and PPV (100%)-High specificity (100%) and PPV (100%)

-Sensitivity only 64.9% & false –ve rate 35.1%-Sensitivity only 64.9% & false –ve rate 35.1%

suggesting that SLNB is suggesting that SLNB is not adequate not adequate as as screening tool screening tool

Predictors of LN Predictors of LN metastasesmetastases

An retrospective analysis of 18445 patients with PTC An retrospective analysis of 18445 patients with PTC staged as pathological T1a staged as pathological T1a

Subjects identified from (Surveillance, Epidemiology and Subjects identified from (Surveillance, Epidemiology and End Results) cancer database from 1988 to 2007 End Results) cancer database from 1988 to 2007

Presence of Presence of ≥≥ 2 factors related to survival: 2 factors related to survival:Male, African American, age Male, African American, age ≥45, extra thyroidal extension, LN ≥45, extra thyroidal extension, LN metastases, distant metastasesmetastases, distant metastases

Other risk factors favoring Other risk factors favoring recurrence:recurrence:

-History of familial thyroid cancer-History of familial thyroid cancer

-Tumour factors-Tumour factors

primary tumour > 2cmprimary tumour > 2cm

multifocalmultifocal

bilateral presence of disease in bilateral presence of disease in thyroidthyroid

BRAF mutationBRAF mutation

BRAF mutationBRAF mutation

BRAF = B-type Raf kinase, located in BRAF = B-type Raf kinase, located in chromosome 7chromosome 7

Most common mutationMost common mutation

conversion of valine to glutamate conversion of valine to glutamate of of amino acid, causing a amino acid, causing a constitutively constitutively active BRAF kinaseactive BRAF kinase

Active BRAF kinase being an Active BRAF kinase being an oncogene in human canceroncogene in human cancer

14 articles, 2470 patients from 9 different countries 14 articles, 2470 patients from 9 different countries

Overall prevalence of BRAF mutation = 45%Overall prevalence of BRAF mutation = 45%

Risk ratios of the following in BRAF mutation +ve patients:Risk ratios of the following in BRAF mutation +ve patients:

-recurrence = 1.93 (95% CI, 1.61-2.32)-recurrence = 1.93 (95% CI, 1.61-2.32)

-LN metastasis = 1.71 (95% CI, 1.50-1.94)-LN metastasis = 1.71 (95% CI, 1.50-1.94)

-Advanced stage (AJCC III/IV) = 1.70 (95% CI, 1.45-1.99)-Advanced stage (AJCC III/IV) = 1.70 (95% CI, 1.45-1.99)

Unilateral vs Bilateral Unilateral vs Bilateral neck dissection neck dissection

Unilateral vs Bilateral Unilateral vs Bilateral

Unilateral pCNDUnilateral pCND

-serves as an indicator of regional -serves as an indicator of regional spreadspread

-tool for selecting patients for -tool for selecting patients for further treatmentfurther treatment

-lower morbidity rates than -lower morbidity rates than bilateral pCNDbilateral pCND

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

Unilateral vs Bilateral Unilateral vs Bilateral

However,However,central lymph node metastases (CLNM) can central lymph node metastases (CLNM) can be found in be found in 25% of contralateral25% of contralateral level VI level VI

Thus, unilateral PND may not be considered as Thus, unilateral PND may not be considered as a therapeutic step in patients with CLNMa therapeutic step in patients with CLNM

Raffaelli M, De Crea C, Sessa L et al (2012) Prospective evaluation of total thyroidectomy versus ipsilateral versus bilateralcentral neck dissection in patients with clinically node-negative papillary thyroid carcinoma. Surgery 152:957–964

Unilateral vs Bilateral Unilateral vs Bilateral Moo and colleagues*Moo and colleagues*

-116 patients with PTC-116 patients with PTC-Tumour -Tumour ≤1cm≤1cm 0 patients with +ve LN bilaterally 0 patients with +ve LN bilaterally Tumour >1cm Tumour >1cm 31% with +ve LN bilaterally31% with +ve LN bilaterally

Skip metastases in contralateral level VI Skip metastases in contralateral level VI present in 5-10% of patients, present in 5-10% of patients, except for PTCs for PTCs <10mm<10mm##

Tumours ≤1cm Tumours ≤1cm unilateral pCNDunilateral pCNDTumours >1cmTumours >1cmbilateral pCNDbilateral pCND

*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

Post operative Post operative radioactive iodine radioactive iodine ablationablation

Post-operative Post-operative radioiodine ablation radioiodine ablation therapy therapy Radioactive iodineRadioactive iodine

-aims to destroy any possible occult -aims to destroy any possible occult residual microscopic thyroid carcinoma residual microscopic thyroid carcinoma to reduce future disease recurrenceto reduce future disease recurrence

Side effectsSide effects-Salivary dysfunction, nasolacrimal -Salivary dysfunction, nasolacrimal duct obstructionduct obstruction-small risk of 2-small risk of 2o o primary malignancies primary malignancies

Post-op ablative Post-op ablative radioiodineradioiodine

Recent consensus:Recent consensus:

Post surgical administriation of Post surgical administriation of 131131II

classified as T1 (diameter < 2cm)classified as T1 (diameter < 2cm)

depends on depends on LN status

T1 tumour, < 1cm, unifocal, N0T1 tumour, < 1cm, unifocal, N0

131131I not indicatedI not indicated T1, N1T1, N1

131131I indicatedI indicated

T1Nx & T1N0 but above 1cmT1Nx & T1N0 but above 1cm

no consensusno consensus

Is prophylactic CND useful in Is prophylactic CND useful in finding the patients with T1N1, finding the patients with T1N1, who were initially thought to be who were initially thought to be T1N0, in which T1N0, in which 131131I would now be I would now be indicated?indicated?

Literature reports a 30% increase Literature reports a 30% increase in the number of patients with T1 in the number of patients with T1 PTC (preoperatively considered to PTC (preoperatively considered to be N0), for whom be N0), for whom 131131I ablation was I ablation was indicated following routine neck indicated following routine neck dissection demonstrating dissection demonstrating unexpected nodal metastases. 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

TNM stagingTNM staging

Levels of evidenceLevels of evidence

AnatomyAnatomyCentral neck compartmentCentral neck compartment

Carty et. al Consensus Carty et. al Consensus Statement on the Terminology Statement on the Terminology and Classification of Central and Classification of Central Neck Dissection for Thyroid Neck Dissection for Thyroid Cancer. Thyroid 2009; vol 19, Cancer. Thyroid 2009; vol 19, no. 11no. 11

TerminologyTerminologyCentral neck dissectionCentral neck dissection

MinimumMinimum

-prelaryngeal-prelaryngeal

-pretracheal-pretracheal

-at least one paratracheal -at least one paratracheal basinbasin

ExtendedExtended-retropharyngeal-retropharyngeal

-retroesophageal-retroesophageal

-paralaryngopharyngeal-paralaryngopharyngeal

(superior to vascular (superior to vascular pedicle)pedicle)

-superior mediastinal -superior mediastinal

(inferior to innominate (inferior to innominate artery)artery)

Possibility of high Possibility of high level evidence?level evidence?

TerminologyTerminology

Therapeutic neck dissectionTherapeutic neck dissectionnodal metastasis nodal metastasis apparentapparent clinically clinically (preoperatively/ intraoperatively) or by (preoperatively/ intraoperatively) or by imaging (clinically N1a)imaging (clinically N1a)

Prophylactic (elective) neck Prophylactic (elective) neck dissectiondissectionnodal metastasis was nodal metastasis was not detectednot detected clinically clinically or by imaging (clinically N0)or by imaging (clinically N0)

Lateral neck LN dissection

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 LNprophylactic lateral neck dissection not recommended

Central compartment LN +vePersonalized decision making

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 necktherapeutic central and selective lateral neck dissection (levels IIa-Vb) recommendedaccessory nerve, SCM, and interal jugular vein preserved

CND reducing recurrence

950 patients with PTC, over a 15 year period Neck dissection (75%)

84% only central compartment

CND reducing recurrence Staging

I (46%), II (26%), III (22%), IV (7%)

RecurrenceLN 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;15:1518-1522

4. Lowers Tg level4. Lowers Tg level

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 1005-7.

Lowers postoperative thyroglobulin levelsLowers postoperative thyroglobulin levels

Undetectable thyroglobulin levelUndetectable thyroglobulin level TT + CND (72%) vs TT (43%)TT + CND (72%) vs TT (43%)

More effective detection of persistent/ recurrent More effective detection of persistent/ recurrent diseasedisease