1. 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

2. 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.

3. Rising incidence of small papillary thyroid carcinoma (PTC)
North America
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

4. 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

5. 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

6. 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

7. “Over-treatment” of latent PTCs?
Prevalence of PTMC = 3 – 18 %
Autopsy series 1966 – Pacini. 2012
Incidence Ca thyroid = 1.6 – 6 /
Registry data 1973 – 1977
Pre-USG era Kilfoy et al. 2009
Ca thyroid related mortality = 0.5 /
Epidemiology database 1973 – 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.

8. 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

9. Ito et al. (2003) - An observation trial for PTMC
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.

10. 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: %
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, % 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

11. 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%

12. 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.

13. 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

14. Sugitani et al. (2010) – Observation trial
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

15. 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

16. 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%

17. 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

18. 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

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

20. 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

21. Thank you!