Joint Hospital Surgical Grand Round PYNEH, 18th April 2015 Role of active observation in the management of thyroid papillary microcarcinoma Lam Shi, RH The topic for my presentation is the role of active observation in the management of PTMC. Joint Hospital Surgical Grand Round PYNEH, 18th April 2015

Definition papillary thyroid microcarcinoma (PTMC) papillary carcinoma ≤ 1cm WHO monograph on histologic typing of thyroid tumors Papillary thyroid microcarcinoma is defined by WHO as papillary carcinomas < 1cm.

Rising incidence of small papillary thyroid carcinoma (PTC) North America 1980 - 2008 PTC 87% PTCs < 2cm It has a rising incidence over the past 2 decades Studies from the united states showed that the recent increase in incidence of thyroid carcinomas is almost exclusively due to the rise of incidence in the papillary subtypes Moreover, out of the newly diagnosed PCs, upto 87% are smaller than 2 cm PTC follicular variant Follicular carcinoma Pellegriti et al. J Cancer Epidemiol 2013 Davies et al. JAMA 2006

Current management of PTMC FNAC: PTC Risk Factors Age > 45 H&N irradiation Multifocal Local / LN invasion Aggressive histology T3 (> 4cm) Any Total thyroidectomy + prophylactic Lv 6 LN dissection  therapeutic MND No The current recommendation for management of PMCs without risk factors for recurrence or mortality. is surgery in the form of total or hemithyroidectomy, wihtout prophylactic central neck compartment LN dissection. Thyroid scan ≤ 1cm 1-4cm Total or Hemithyroidectomy Total thyroidectomy +/- RAI McLeod. Lancet 2013 4

Excellent outcomes of surgical treatment for PTMC Author, year Follow-up (Year) No. of patients Recurrence Mortality Noguchi, 2011 10 867 1% 0.2% Baudin, 1998 7.3 281 4% 0% Ito, 2003 626 5% Hay, 2008 17.2 900 6% 0.3% Chow, 2003 203 7% And the outcome of surgical treatment for PTMC is excellent. With previous surgical series showing a very low recurrence rate of 1 – 7% and very low mortality rate over a period of 7 – 17 years after surgery. 5

Favorable outcome of incidental vs non-indicental PTMC Author N Multicentric (%) Bilateral Lymph node met (%) Distant Recurrence (%) Mortality I NI Baudin 281 30 61 13 23 22 91 8.6 2.1 7.6 Pellegriti 299 25 39 15 16 45 0.7 4.7 ns Roti 243 19 36 11 20 4 2 Lo 184 12 32 2.7 3.6 Further more, many studies has shown that PTMCS detected incidentally after surgery, represented by numbers in yellow, has more favorable pathological features such as multicentricity, bilaterality, lymph node or distant metastasis. So, the prognosis of incidental PTMCs may have a lower recurrence and mortality rates compared to the non-incidental PTMCs I = incidental; NI = non-incidental 6

“Over-treatment” of latent PTCs? Prevalence of PTMC = 3 – 18 % Autopsy series 1966 – 1990 Pacini. 2012 Incidence Ca thyroid = 1.6 – 6 / 100 000 Registry data 1973 – 1977 Pre-USG era Kilfoy et al. 2009 Ca thyroid related mortality = 0.5 / 100 000 Epidemiology database 1973 – 2002 Davies et al. 2006 Therefore, when papillary microcarcinomas are detected incidentally before operation, some centers advocate a more conservative approach for the believe that only very few of these tumors will manifest during a patient’s lifetime This is supported by the finding that PTMC is a very common condition in post-mortem examination, giving an estimated “prevalence of 3 – 18% However, during the same period, the incidence of thyroid cancers diagnosed is very low. Moreover, despite an increased detection and treatment of small PCs, the cancer related mortality remained static. So this has given rise to the question of whether we are over-treating PTMCs that would have remained latent during patient’s life-time.

Can PTMCs be observed without immediate surgery ? Hypothesis A significant proportion of PTMCs are indolent and may not manifest in one’s lifetime Proposal To observe newly diagnosed incidental PTMC Operate only when lesion showed sign of progression Question Safety of delaying surgery until lesion showed evidence of progression ? based on the hypothesis that incidental PTMCs are slow growing and may remain latent in one’s lifetime, Two Japanese groups proposed putting newly diagnosed PTMCs under observation and perform surgery only when they showed evidence of disease progression. And they sought to find out whether it is oncologically safe to delay surgery after observation 8

Ito et al. (2003) - An observation trial for PTMC 1993 -2001 732 patients with FNAC diagnosed PTMC exclusion (570): RLN palsy tumor close to trachea / RLN suspicious LN in lateral compartments high grade malignancy patient’s choice 162 patients for observation USG every 6 – 12 months surgery if tumor progresses ≥ 10mm, new suspicious LN in lateral compartment The first study is performed by Ito et al. from Kuma hospital during the period 1993 – 2001 732 patients are diagnosed to have PTC with FNAC 570 are excluded due to … 162 patients included for observation by USG surveillance And if they demonstrate tumor progression to beyond 10mm and develop clinically detected LN in lateral compartment.

Ito et al. (2003) - An observation trial for PTMC 162 patients followed-up for 18 – 113 months (mean 47) Tumor size no change at all time points: 70 - 83% increase to ≥ 10mm: 18 (11%) Lymph node (lateral compartment) 2 (1.2%) newly detected by USG Operation rate 56 patients (35%) operated At 19 – 56 months after observation indications: disease progression (9), ? patient’s choice (47) So these 162 patients are followed-up for a period of 18 – 113 months It is found that Given a number of patients at any timepoint of follow-up, 70 - 83% of them will have tumor size remained unchanged since the beginning of follow-up Overall 18 patients (11%) has tumor progressed to beyond 10mm However the gap between no change and increase to more than 10mm is not addressed in the result. As for lymph node involvement 2 patients newly developed suspicious lymph nodes on USG in one of the lateral neck compartments Eventually 35% of the patients underwent operation at 19 – 56 months after observation The indication for surgery is disease progression in 9 patients and patient’s preference in 47

Ito et al. (2003) - An observation trial for PTMC % TNM staging (AJCC 6th Ed. 2002) pT pN M 63 100 1a 50 32 1b 41 5 2 3 4a < 1cm 1 – 4 cm > 4 cm Extra-cap invasion The TNM of the operated patients are shown in the table Most of the tumors remain small and intra-thyroidal At that time the AJCC 6th edition of TNM staging is followed Microscopic LN met is not uncommon with 37% patients showing lymph nodes in the central or lateral compartments In any case the outcome of the operated group is good with a recurrence rate of 2.6% and no mortality recorded. Clinical outcome local recurrence 2.6% distant metastasis / mortality 0%

Ito et al. (2013) – Age predicts progression follow-up 1.5 – 19 years (mean 5 years) 58 (4.6%) with tumor enlargement; 43 (3.5%) > 12mm 19 (1.5%) LN metastasis during observation 10-year rates size enlargement – 8.3% (6.8% > 12mm) new LN during observation – 3.8% Age < 40 as an independent predictor 191 (16%) underwent operation post-operative follow-up 75 months Local recurrence 0.5% Mortality 0 The Kuma group has since been adopting the management protocol for the past 2 decades and has publish a larger series including > 1000 patients With a follow-up between 1.5 – 19 years 4.6% of patients showed tumor enlargement and 3.5% progress to non-microcarcinomas And clinically detectable lateral compartment lymph node metastasis occurred in 1.5% of patients. Giving a 10-year rate of progression to clinical disease of 6.8%, clinical lymph node metastasis in 3.8% A multivariate analysis showed that age < 40 is a significant predictor of disease progression and size enlargement 16% of the cohort population eventfually had operation and the outcome upto 75months after operation is excellent with local recurrence rate of 0.5% and mortality of zero.

Tumor enlargement > 12mm These are the graphs of Time to event analysis showing the effect of age on tumor enlargement, progression to clinical disease and newly clinically detected LN New lymph node 13

Sugitani et al. (2010) – Observation trial 1993 -2001 230 patients chose initial observation 300 PTMCs (multifocal in 48 pts) Mean follow-up 60 months 7 patients lost to follow-up, 6 patients died of other disease Surgery if tumor growth towards adjacent structures, increase in size, LN / distant metastasis, patient’s preference Another group from Tokyo has also initiated an observation trial with similar design during the same period as Ito’s first study. With 230 patients carrying 300 PTMCs observed with regular USG for a mean period of 60 months

Sugitani et al. (2010) – Observation trial Tumor size no change / decrease: 93% increase : 7% (22 patients) Lymph node metastasis - 1% Operation rate 16 patients (7%) indications: disease progression (12), patient’s choice (4) ? 6 patient with increased size not operated Recurrence / mortality: 0 Outcome of Sugitani’s study Tumor has increased in 7% of the patients and clinical lymph node metastasis detected in 1% of the patients 7% of patient underwent operation for indications of disease progression and patient’s preference There has been no recurrence or mortality recorded

Summary Natural history – 10 years (Ito) 8.3% increase by > 2mm 3.8% progress to > 12mm 3.8% develop new LN in lateral compartment Operation rate: 7 – 16% (Ito, Sugitani) Total thyroidectomy 13 – 50% “limitted” thyroidectomy 50 – 87% Lymph node dissection Therapeutic lateral ND 1% - 18% Prophylatic CND 6 – 100% High incidence of microscopic lymph node (38%) and multifocality (69%) in the operated cohort Outcome of delayed surgery Local recurrence: 0.5 – 2.6%; Mortality: 0%

Immediate vs delayed surgery for incidental PTMC Author N Multicentric (%) Bilateral Lymph node met (%) Distant Recurrence (%) Mortality Baudin 281 30 13 22 2.1 Pellegriti 299 25 15 16 0.7 ns Roti 243 19 11 4 Lo 184 12 Ito 186 69 38 0.5 17

Limitation Study design Single-centered case series Small sample size of operated group for detection of rare events Patient’s choice to operate  increased denominator with non-progressive lesions  mitigate recurrence rate Duration of follow-up relatively short Data quality Defaulted cases not explicitly described Some patient has tumor enlargement but not operated Generalizability Dedicated USG surveillance program Cultural issues 18

JSTS / JAES Guideline 2011 “ observation without immediate surgey can be an option for patients with low-risk papillary microcarcinoma”

Conclusion Role of initial observation a “step” rather than “option” to futher risk-stratify low-risk PTMCs into progressive and non-progressive lesions may avoid surgery for indolent tumors in patients with limitted life expectancy Practical considerations ? reliable USG surveillance programme patient anxiety / quality of life 20

Thank you!