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

-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

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 ?

What is the rationale supporting routine central neck dissection?

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 2006:141:5:489-494

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 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 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

What are the arguments against prophylactic central neck dissection ?

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

What is the current evidence available?

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

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)

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

Meta-analysis Hypocalcaemia & RLN injury

Meta-analysis Hypocalcaemia & RLN injury Relative risk 95% CI Hypocalcaemia Temporary Permanent 2.52 1.82 1.95-3.25 0.51-6.5 RLN injury Transient 1.44 1.14 0.59-3.55 0.46-2.83

Locoregional Control Survival

-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

Retrospective cohort study, 10 years , 640 patients 282 TT (1993-1997) vs 358 TT/pCND (1998-2002) University Medical College in Krakow, Poland, between 1993 - 2002 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)

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

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

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)

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

Recommendations/ Guidelines

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

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

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

Sentinel LN Biopsy

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

Predictors of LN metastases

Presence of ≥ 2 factors related to survival: An retrospective analysis of 18445 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

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.

BRAF mutation

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

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, 1.61-2.32) -LN metastasis = 1.71 (95% CI, 1.50-1.94) -Advanced stage (AJCC III/IV) = 1.70 (95% CI, 1.45-1.99) 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

Unilateral vs Bilateral neck dissection

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 1980-2010 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 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

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

Post operative radioactive iodine ablation

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

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

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

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

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

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.

Levels of evidence

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

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)

Possibility of high level evidence?

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)

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 LN prophylactic lateral neck dissection not recommended Central compartment LN +ve Personalized 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 neck therapeutic central and selective lateral neck dissection (levels IIa-Vb) recommended accessory 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%) 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;15:1518-1522

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 6-12 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 1005-7.