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Increasing Diagnosis of Micro-Papillary Thyroid Cancer (<1 cm )
New Trends in Management
Vahab Fatourechi MD
Mayo Clinic
Tehran EMRI
2015
Learning Objectives
• Recognize different clinical presentations of
micropapillary cancer
• Be familiar with trends in less aggressive
management of incidental occult papillary
cancer
• Short reference to 2015 ATA Guidelines
NOT ALL THYROID CANCERS ARE EQUAL
•
•
THYROID
CANCER
FREQUENCY
MORTALITY
Papillary
85%
1-2% at 20 years
Follicular
11%
10-20% at 10 years
Medullary
3%
25-50% at 10 years
Anaplastic
1%
90% at 5 years
1 patient in 100 with PTC will die due thyroid cancer at 20 years
1 patient in 1000 with low-risk PTC will die at 20 years.
Surveillance Epidemiology and End Results. http://seer.cancer.gov/statfacts/html/thyro.html
Papillary Cancer Cell Types Associated with
Aggressive Behavior
•
•
•
•
•
•
Columnar cell PTC
Insular cell PTC
Tall cell PTC
Trabecular PTC
Higher grades of PTC : Grade 2-4 (majority are grade1)
Comment : Most of these present clinically and rarely
micro-papillary
RELATIVE SURVIVAL RATES AT 5 YEARS
Thyroid
97.5%
Low Risk
99.9%
1 patient in 1000 affected with
low-risk thyroid cancer and
treated will die due to thyroid
cancer
Surveillace Epidemiology and End Results.
http://seer.cancer.gov/statfacts/html/thyro.html
Slow progression or
regression
Dying of thyroid carcinoma
(cumulative %)
Cause-Specific Mortality Rates in FCDC
Mayo Data
40
90
ATC
FTC
30
HCC
20
10
PTC
0
0
5
10
15
Years after initial treatment
20
25
PTC Survival by TNM Stage
Mayo Data
Surviving papillary thyroid
carcinoma (%)
100
80
n=2,284
1940-97
P=0.0001
60
TNM stage
40
I 1,360
II
493
III
399
IV
32
20
0
0
5
10
15
Years after initial treatment
20
25
No Change in Mortality over 6 Decades
in PTC (Mayo Clinic Data)
•
•
•
•
•
2444 cases 1940-1999
No change in cause specific mortality
No change in tumor recurrence rate
Remnant RA ablation did not change outcome
For low risk (MACIS <6) CSM 1% and recurrence
15%
Hay ID, World J Surg 2002: 26;879
Endo Pract 2007 :13 521
Thyroid Carcinoma:
1992- 2014 Estimates
• Incidence increased from 20,000 to
62,800
• 1992
5/100,000
• 2014
15 /100,000
• Almost all of increase is papillary thyroid
cancer: over 95% of all thyroid cancers
• Deaths n=1850 , Not changed
Davis L,eta l JAMA Otolaryngol Head Neck Surg 2014;140: 317
Increasing Incidence of
Thyroid Cancer Worldwide
• .
Rising Thyroid Cancer Incidence
Olmsted County Minnesota (Mayo data)
•
•
•
•
Comparesd1990-1999 to 2000-2012
7.1 /100000
Increased rate to 13.7
53% asymptomatic incidental finding
Neck imaging 36%, incidental for thyroid benign
disease Surgery 26%, found on routine exam
20%, investigation for unrelated symptoms12%
• Exclusion of incidental brings rate to 6.3%
•
Brio JP et.al, Abstract ATA meeting Oct 2014
Detection of Reservoir
Surveillance Epidemiology and End Results. http://seer.cancer.gov/statfacts/html/thyro.html
Detection of Reservoir
Rate per 100 000
US-guided aspiration of
thyroid nodules
Increased in
CT/MRI use
Widespread use of
thyroid ultrasound
Fine-needle aspiration
for thyroid nodule
Brito JP. BMJ 2013;347:f4706
South Korean Experience in n
Routine Thyroid Cancer Screening
• In 1999 In south korea national cancer
screening program started thyroid was not a
part but most provided added US of neck for
small fee
• Diagnosis of thyroid cancer increased 15 fold
• 40,000 diagnosed in 2011, death rate
annually 300-400
• Death from thyroid cancer did not change
H.S Ahn et al NEJM Nov 2014 :731:1765
Rate (per 100,000 population)
Thyroid-Cancer Incidence and Related
Mortality in South Korea, 1993-2011
Thyroid-cancer
incidence
Incidence of
papillary thyroid
cancer
Thyroid-cancer mortality
Ahn et al: NEJM 371;19, 2004
Thyroid Cancer Reservoir



Sectioned thyroids from 101 autopsy specimens, 1-3 mm slices.
Found PTC in 36% of glands, no prior history of thyroid disease.
Speculated that if sectioned carefully enough, many more would
have been found, perhaps all.
Harach HR. Cancer 1985;56:531-8.
Incidental Thyroid Micro-cancer In
Autopsy
•
•
•
•
Argentina ; n=100,
13.6% men , 7.3% women
Spain 5.3%
Bellarus
9.3%
• Greece:
7.7 %
• Sweden:
8.6%
Cancer ;1989;64;1888
Martinez – Tello Cancer 1003; 71;4022
Fufrmanchuck AW Histopathology, 1993,4;319
Mitselou, A , Anticancer research 2002 22;427
Incidental Thyroid Micro-cancer In
Autopsy
•
•
•
•
•
Pub Med Search 2011
21 countries, 7897 autopsies
English literature
0.14 % MTC
7.6% PTC all <0.5 cm no lymph nodes
•
Conclusion : This should be considered in
epidemiologic studies and screening
recommendations
Valle LE JCEM 2011 96: 109
Incidental Micro cancer in Thyroidectomy
for Benign Disease
• 15%
• 8.8%
• 2.2 % in GD
•
•
•
•
•
•
12%
9.3%
5.7 %
26%
16.7%
10%(GD)
Siassakos Singapore med J 2008
Femando ,Cylone Med J 2009
Anilam. Rev Med Schir Soc Med Nallasi 2008
Bradley DP, Surgery 146: 2009
Costamagna G , Surg 2013
Bombil I, S Afr J Surg 2014
Ergin AB, Amer J otolaryng, 2014,
Fink, Mod path 1996,9;816
Karagulle E, Int Surg 2009;94;325
Mean 12%
Thyroid Incidental Micro-cancer
FDG- PET
•
•
•
•
N=
Focal uptake
Confirmed PTC
Malignancy
2105
1.7% (35)
8
3 3% on PET Pos
Prichard RS Ir med J ,2011:104;177
Thyroid Cancer in Ultrasound Screening
•
•
•
•
•
•
•
N=1140, Hong Kong
No thyroid symptoms routine screening
44%
nodules
FNA
in 258 patients
2.3%
FNA suspicious for malignancy
1.2%
Histologic PTC
Conclusion: If routine screening is used 4.2 million
in USA
Yuen AP Head and Neck 2011, 33;453
Detection of Reservoir
• If we assume only 6% as prevalence of micro PTC:
– Predicts 18 million cases in population
– SEER database reports only 0.5 million prevalence of all
types and sizes of DTC
– We have yet only seen the tip of the iceberg
– In current practice, PTC will be the most rapidly growing
cancer diagnosis for years to come.
Ross and Tuttle. Thyroid 24:3-6 2013
Likelihood of Death from Histologic Thyroid
Cancer
• Estimated death 1780/year
• with conservative estimate 7 % of USA population
(22) million have micro PTC
• Thus likelihood of death from all thyroid cancer is
79 per one million histologic thyroid cancer
(0.0079%)
• Almost all mortality is from clinical thyroid cancer
not occult. Mortality would be close to zero for
occult undiagnosed thyroid cancer
Possible Causes of Increasing
Incidence
•
•
•
•
•
•
•
Radiation Exposure
Iodine intake
Obesity/Diabetes
Autoimmune Disease
Estrogen/Progesterone
Reduced smoking
But most likely Increasing use of imaging
technologies
– Overdiagnosis
Variable Presentation of Micro PTC
• Found on thyroid surgery for benign disease
• Occult nodule found on conventional imaging done
for other purposes
• PET positivity thyroid done for other purposes
• Less than 1 cm nodule palpable on a lean neck ,
usually the isthmus
• Evidence of neck node metastases with negative
thyroid US or mica nodule
• Evidence of distant metastases with benign
appearing US or micro nodule in thyroid
Case 1
Incidental PTC and benign thyroid
nodule
• .
A
B
Lt Longitudinal
FNA shows:
A, PTC
Case-2
• .old lady a palpable
66 year
level IIb Rt FNA positive
for PTC
US 4 mm hypoechoic nodule
Rt lobe no suspicious
features. 2.3 cm nodule
Rt upper neck with proven
FNA shows PTC
Rt upper neck PTC Mets
RT lobe transverse
Case-2
Rt lobe longitudinal
Case-2
• Surgery: bilateral thyroidectomy 3 mm PTC
Rt upper pole and 2 mm left lower pole. Other
than palpable 2.3 cm nodule 35 nodes IIa ,
II,II and IV, VI were negative
• RAI therapy
• No recurrence , Tg undetectable at one year
F/U
Case-3
•
A female in 2000 at age 59 presented with
multiple lung nodules biopsy was PTC
• US of thyroid showed benign appearing less
than 6 mm nodules, no lymphadenopathy
• Bilateral thyroidectomy, only 5 mm Occult
PTC Rt lobe
• One central node compartment positive
Case -3
• Remnant ablation, 2 doses of 200 mCi I-131
• Good uptake in lung metastases in 2001 and
2002
• Last WBS negative in 2005
• Lung nodules stable less than 6 mm 20042014
• Excellent quality of life at last visit in Nov 2014
Outcome of 900 Micro PTC
1994-2004 (Mayo Data)
•
•
•
•
•
•
Median size 7 mm
85% bilateral lobectomy, RAI in 17%
30% neck node positive
0.3% distant mets, 0.6% incomplete excision
0.3% died of PTC, Recurrence rate in 40Yrs 6%
Higher recurrence in multifocal tumors, and node
positives
• 99% not at risk of distant spread or mortality
• RAI or bilateral lobectomy did not change outcome
Hay ID, surgery; 2008;144:980
14045 Micro Papillary Cancer in Korea
Single Institution 1986-2013
•
•
•
•
•
Total thyroidectomy 47%, less than total 53%
Central compartment node 27% lateral neck 4.9%
10-20 yrs. survivals 98% and 94%
10-20 yrs. disease free survivals, 97% and 94%
No difference between thyroidectomy total and less
than total
Lee c et.al. Presented in OCT 2014, ATA Meeting
Reported Complications of Thyroid Surgery
30
Surgery 140:1000-1005, 2006
Arch Surg 383:167-169, 1998
Ann Surg 245:604-610, 2007
Cancer 115:251-258, 2009
25
20
LNI
15
HPT
T LNI
10
5
T HPT
%
0
LB
TT
Brito JP, et. al.. BMJ 2014 in press.
TT+PLND
Less-aggressive treatment options for Micro-papillary
Thyroid Cancer
• Lobectomy vs. bilateral surgery
• Targeted ablative procedures
– Percutaneous ethanol ablation
– Radiofrequency ablation (RFA)
– Cryoablation
• Active surveillance
Observation for Micro PTC
Better
Active surveillance
AWARENESS ABOUT THE EXISTENCE OF
TREATMENT OPTIONS
Ito Y, World J Surg 2010;34:28-35
Active Surveillance for Micro-PTC
Age of Patient
• 1235 patient chose observation 1993-2011
• Progression lowest in over age 60
• Highest in the younger <age 40
• Young age independent predictor of progression
• None of 1235 had distant mets or died from PTC
• 4% had TSH suppression, except one all clinically stable191
had surgery
• Conclusion: Older patients with Micro PTC best
candidates for obserrvation,
• For younger under observation, it is not too late to surgery if
progression
Ito Y et al thyroid 2014: 25:27
Active Surveillance of Micro-PTC
20 years
F/u
>3 mm growth
Age effect
Ito Y, Thyroid 2014
Lymph node mets
Age effect
Distinct Types of Micro PTC
Under Observation
• I- Incidental finding – observed and no change in size
• II- Increase in size during observation – Lobectomy is
suggested
• III- Clinically symptomatic, needs more aggressive
management
• 230 out of 244 accepted observation\300 lesions: 5 year
observation: 7% increase in size, 90% unchanged 3%
decreased: Conclusion: Observation 95% are type I and
can be observed
Sugitani I etal World I surg 2010 ;34:1222
Tumors not Candidate for Active
Surveillance
•
•
•
•
•
•
•
•
Peripheral and bulging
Close to trachea with angle over 90 degrees
Evidence of node or distance mets
Multifocal?
Family history of non medullary thyroid cancer
History of radiation exposure
PET positive tumors?
Patient preference
Minimally Invasive Intervention
• Ethanol ablation
• Radio-frequency ablation
• Cryoablation
Ethanol Ablation for Micro-papillary Thyroid
Cancer –Mayo pilot study
13 patients, 9 F, 4 M, 5 with co-morbidity, ages 36-86
Tumor sized 4-13 mm, injection of 95% alcohol, 2 injections in
subsequent days, Ethanol 0.45-1.25
F/u 0.3-4.4 yrs. Medium 1.6 yrs.
Median volium reduction 76 % all shrunk 4 disappeared
Conclusion: For micropapilalry thyroid cancer, patients not
comfortable with surgery or active survellance ethanol ablation
may be a n attractive minimally invasive option
Hay, ID et al , ITC 2015
2015 ATA Guidelines
Changing Diagnostic and Treatment Recommendation
•
•
•
•
•
Less aggressive detection
Less aggressive surgery for low risk PTC
Less RAI therapy for remnant ablation
Lower dose RAI for remnant ablation
Central compartment Node excision optional
for Low risk PTC
Haugen et al Thyroid 2015
2015 ATA Guidelines for Thyroid Nodule
Haugen et al, Thyroid, 2015
Nodule TSH
normal or high
US
High
suspicion
Intermediate
pattern
FNA
>1 cm
Low
suspicion
FNA
>1.5 cm
Pure cyst or
benign pattern
No FNA
Very low
suspicion
FNA
>2 cm
2009 ATA Guidelines
Recommendation
• For >1 cm initial surgery bilateral near -or total
unless contraindications
• Lobectomy for <1cm, uni-focal intra-thyroidal low
risk PTC unless prior head and neck radiation
or lymph node involvement (recommendation A)
Thyroid ; Nov 2009
2015 ATA Guidelines for Micro-papillary
Thyroid cancer
• Less than 1 cm suspect nodule no FNA and
observe particularly in older
• When diagnosed R/O metastasis , if unifocal ,
no radiation history or syndromal PTC:
lobectomy and no lymph node sampling
• May consider active surveillance, in certain
situations
• 1-4 cm no other risks lobectomy a
Haugen et al. Thyroid 2015
consideration
Evaluate and Consider Less-aggressive
Treatment Options
• Lobectomy vs. bilateral surgery
• Emerging targeted ablative procedures
– Percutaneous ethanol ablation
– Radiofrequency ablation
– Cryoablation
• Active surveillance
Management of Occult Papillary Thyroid
Cancer
• For unilateral incidental :
Lobectomy if unifocal or multifocal
Observation may be an option
• For incidental found on surgery less than 1 cm
Lobectomy and no radioactive iodine, No data if T4 therapy is needed
• With lymph node metastasis or distant metastases at
presentation
Near total thyroidectomy and RAI remnant ablation for stages II
(younger than 45) and Stages III and IV (older than age 45)
• For PET positive incidental PTC
Perhaps more aggressive, but data is needed
Management of Occult Papillary Thyroid
Cancer
Special situations when more aggressive bilateral near
total or total thyroidectomy may be needed
• History of head and neck radiation
• Non- medullary hereditary differentiated thyroid
cancer or family history in first degree relatives
• PTC larger >1.5 cm or extra thyroidal extension
• Syndromic FCDTC
• PTC found on PET? (data needed)
Issues Needing More Data
•
•
•
•
If observation is chosen should T4 therapy given?
If lobectomy is done should therapy with T4 given?
Should multifocal PTC be treated differently?
Should non- invasive ehanol or RFA ablation be a standard
option for diagnosed occult PTC
• Should we be less aggressive in performing FNA for less
than 1 cm suspect incidental PTCs specially in elderly ?
• Need confirmation that older asymptomatic patients with
Micro PTC are not subject to higher age related risk
Micropapillary Thyroid Cancer Found
on PET scans
•
•
•
•
•
12 patients with incidental PET positive PTC
25% multifocal
66% extra thyroidal extension
41% angioinvasion
16% lung mets
Conclusion: 92% had intermediate or high risk
per ATA criteria. Thyroid carcinomas detected
by18-F-FDG PPET have aggressive histology
and likely worse prognosis
Pedro Marques et. al. Endo Practice 2014; 20: 1129
CHOOSING THE “RIGHT” TREATMENT
A 44-year-old executive
concerned about future
metastatic disease might opt
for thyroid surgery
A singer, or a public speaker,
concerned about the possible
perioperative damage to
voice may opt for active
surveillance
Conclusion-1
• Worldwide increase in papillary thyroid cancer is
mostly related to increased imaging and finding of
non–significant micro -PTC
• Incidentally discovered micro PTC in thyroidectomy
for benign disease can be considered not clinically
significant and no further action is needed
• For PTC less than 1.0 cm active surveillance may
be offered in future if acceptable to the patient
Conclusion-2
• Decision for FNA of a <1.5 m nodule if
incidentally discovered should be more
conservative following 2015 ATA guidelines
• Controlled studies of active surveillance vs.
surgery or minimally invasive procedure such as
alcohol ablation are underway
• If surgery is chosen for incidental micro PTC
Lobectomy should be adequate and central
compartment node sampling may not be needed
Conclusion-3
• Rare cases of Micro PTC with significant neck
node mets or distant mets exist. But they are
usually diagnosed by clinical metastasis and
primary source may be occult and their
management is according to the staging of the
cancer
That is it!
Thank YOU
20022002
Incidence of thyroid
cancer in multiple
countries, 1985 vs.
2002
19851985
Brito JP. BMJ 2013;347:f4706
Clinically “silent” disease
Clinically “silent” disease
IDENTIFICATION OF PATIENTS AT
LOW RISK
No family history of thyroid cancer
No personal history of radiation
exposure
PTCC
LOW
RISK
PTC
<1.5 cm lesion compatible with
papillary thyroid cancer on cytology –
no unusual histology
No evidence of extraglandular
extension or lymph node metastasis
LOOKING AHEAD
• The term microPLIC should also be tested to ensure that it
promotes careful deliberation and patient-centered treatment.
• RCT of active surveillance vs. thyroid surgery and other potential
treatment options for PLICs
• Role of decision aids to avoid overtreatment for PLICs
• Interventions to prevent overdiagnosis and overtreatment of
PLICs
– Molecular or other markers of aggression
– Less invasive treatment options – PEI, RFA, Laser, etc
• Role of guidelines and recommendations to overcome
overdiagnosis and overtreatment
Recent rise in thyroid cancer incidence is related to discovery of a reservoir of
previously unrecognized subclinical disease: a population-based study in
Olmsted County, Minnesota during 2000 through 2012
2000-2012
1935-1999
(263)
2000-2012
(213)
46 (17.8)
46.3(14.9)
49.6 (14.9)
42.7 (14.14)*
193 (73)
149 (79)
79 (70)
70 (70)
1.98 (1.6)
1.76 (1.2)*
1.3 (1)
2.26 (1.2)*
MACIS score (Mean, SD)
4.6 (1.5)
4.7(1.3)
4.6 (1.2)
4.7 (1.4)
MACIS score < 6 ( N, %)
184 (86)
175 (88)
94 (87)
81 (89)
Papillary ( N, %)
215 (82)
199 (93)*
108 (96)
91 (91)
Follicular( N, %)
15(6)
6 (3)
3 (2)
3 (3)
Hurtle( N, %)
19(7)
1 (0.5)
1 (1)
0 (0)
Medullary( N, %)
38 (2)
4 (2)
1 (1)
3 (3)
Metastatic( N, %)
0 (0)
1 (0.5)
0 (0)
1 (1)
Anaplastic ( N, %)
6(2)
0 (0)
0 (0)
0 (0)
Lymphoma( N, %)
0 (0)
2(1)
0 (0)
2 (2)
Age at Diagnosis in years (
Mean, SD)
Female N(%)
Size of tumor ( Mean, SD)
Clinically occult
(113)
Clinically recognized
(100)
Type of thyroid Cancer
Thyroid Incidental Micro-cancer In
Autopsy
:
• Finland
n=101
• 35% thyroid cancer
• ( 2-3 mm cuts) (range 0.1 mm15mm) 67% under 1 mm
Thyroid Cancer Reservoir
First author, year
Mortensen 1955
(& Woolner)
Harach 1985
Lang 1988
Ottino 1989
Martinez-Tello 1993
Solares 2005
Country
Method
Women
N (%)
Men
N (%)
USA
(Mayo Clinic)
All nodules
318/821
(38%)
191/538
(34%)
Finland
All of gland
13/48
23/53
(27%)
(43%)
‘Suspicious areas’
only
24/421
39/599
(6%)
(7%)
not clearly defined
3/41
8/59
(7%)
(14%)
6/34
16/66
(18%)
(24%)
1/34
2/116
(3%)
(2%)
Germany
Argentina
Spain
Guatemala
All of gland
‘Suspicious areas’
only
IDENTIFICATION OF PATIENTS AT
LOW RISK
10
<1 cm
Rate per 100 000
8
6
1-2.5 cm
4
2
>3 cm
0
1975
1979
1983
1987
1991
1995
1999
2003
2007
Surveillance Epidemiology and End Results. http://seer.cancer.gov/statfacts/html/thyro.html
Case-1
What should be management?
•
•
•
•
1- Radioactive iodine remnant ablation
2-Suppressive thyroxine therapy to TSH< 0.1
3-Annual thyroid US for 5 years
4-No follow up neck US is needed
Case-2
1. Patient needs completion thyroidectomy
2. Patient needs central compartment node
sampling
3. If FNA of the larger nodule was benign
observation might have been an option
4. None of the above
Study Points to Overdiagnosis of Thyroid Cancer
New York Times, November 6, 2014
Korea's Thyroid-Cancer “Epidemic”
— Screening and Overdiagnosis
N Engl J Med 2014; 371:1765-1767 November 6, 2014
Thyroid cancer (PTC) is now the
most
Prevalent cancer in Korea.
Study Points to Overdiagnosis of Thyroid Cancer
New York Times, November 6, 2014
Korea's Thyroid-Cancer “Epidemic”
— Screening and Overdiagnosis
N Engl J Med 2014; 371:1765-1767 November 6, 2014
Thyroid cancer (PTC) is now the
most
Prevalent cancer in Korea.
New Thyroid Cancer Cases per year - USA - 1974-2012
60000
50000
New Cases (N)
Total (N)
Male (N)
40000
Female (N)
30000
20000
10000
0
1970
1974
1978
1982
1986
1990
Year
1994
1998
2002
2006
2010
Incidence Rates for Thyroid Cancer
Rate per 100 000
14.3
4.8
Surveillance Epidemiology and End Results. http://seer.cancer.gov/statfacts/html/thyro.html
Differentiated Thyroid Carcinoma
• Follicular cell derived
thyroid carcinomas
(PTC and FTC)
comprise up to 95% of
all thyroid carcinomas
• The vast majority of
these tumors are well
differentiated
Grebe & Hay 1995
Papillary
Medullary
Follicular
Other
3% 2%
10%
85%
Case-1
• 32 year old lady seen in 2012 with hyperthyroidism,
• Thyroid US: Heterogenous pattern and tiny
nodularity not suspicious. Isotopic scan diffuse
enlargement, serology consistent with Graves
• Treated for 2 years with antithyroid medications
poor response
• Surgery in 2014 bilateral diffuse hyperplasia. Left
lobe had 1.3 cm follicular variant of PTC
• What should be management?
Case -2
68 year old with a palpable
newly found 2.5 cm nodule in the left
Case-2
• Lobectomy done
• The 2.5 cm lesion was follicular benign
adenoma
• 5 mm PTC in the left lobe and also 2 other
foci of 2 and 3 mm PTC
Increasing Diagnosis of Micro-papillary Thyroid Cancer
New Trends in Management
No Disclosure
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