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Isabel ROCA, Montserrat NEGREJoan CASTELL
THYROID CANCER IN CHILDREN
HU VALL HEBRONBARCELONA
• ADULTS• males 1,2-2,6 cases /100.000• females 2,0-3,8 cases /100.000
Thyroid nodules in children and adolescents:• although rare, • have a higher rate of malignancy than in adults
Feinmesser et al, J Ped End & Metab 1997; 10: 561-568
THYROID CANCER IN CHILDRENEPIDEMIOLOGY
• 0,02-0,3 / 100.000 children • 3-6% of all thyroid cancers• 3rd most common solid tumor < 20 y • 1.1 % cancer deaths• only 8% die due to thyroid cancer• rare in children below 16 y • exceptional before 10 y
THYROID CANCER increase in incidence ?
American Society of Cancer, 2006
RISK FACTORS• radiationINCREASE IN DIAGNOSTIC ?• screening• US, cytology
THYROID CANCER IN CHILDREN
1st INCIDENCE PEAK• external neck irradiation for benign conditions
Tinea capitis, acne, chronic tonsilitis, thymusenlargement
2nd INCIDENCE PEAK• environmental contamination with radiactive iodine
due to Chernobyl catastrophe in 1986• sharp increase in thyroid cancer incidence
Mainly in children < 5 y at exposureOnset < 14 y
• Children < 5 y• Girls more than boys
higher sensitivity to effects of ionizing irradiation
EARLY 1990’s
MID 20th CENTURY
• In most children thyroid cancer is already at an advanced stage of the disease at the moment of diagnosis
• However, in this age group, the outcome of thyroid cancer is good
THYROID CANCER IN CHILDREN
Harness, 1992Dottorini, 1997
Thompson, 2004
• Palpable thyroid nodules 73 – 87 %
• Nodules in children are more often malignant than in adults• > 4 cm: 36% children vs 15% adults• < 1 cm: 9% children vs 22 adults
THYROID CANCER IN CHILDREN
Vall Hebron series in children 1980-2005
80 patients 3-18 years average 13.4 y +/-3.6 SD28 boys 35 % (X 12 y)52 girls 65 % (X 14 y)
<5a
5a-6a
7a-8a
9a-10a
11a-12
a
13a-14
a
15a-16
a
17a-18
a
0246810121416
girlsboys
3 10 18 years
THYROID CANCER IN CHILDRENEPIDEMIOLOGY
• higher incidence in girls: ratio female / male 2:1• few cases under 5 years• progressive increase with age: peak at puberty
0
5
10
15
20
Female 0 2 3 4 6 14 8 16Male 2 3 2 3 2 5 9 3
<5 y 5 y-6 y 7 y-8 y 9 y-10 y 11 y-12 y 13 y-14 y 15 y-16 y 17 y-18 y0
10
20
30
40
50
Female 9 44Male 10 19
<=10 y > 10 y
• Under 10 years: girls = boys • Overall incidence in females was higher than in males (≈ 2/1)• Progressive increase of incidence with age, with peak at puberty, specialy in girls
THYROID CANCER IN CHILDRENSEX AND AGE AT DIAGNOSIS
Vall Hebron series
Handkiewicz-JunakJ Nucl Med 2007; 48:879–888
0
20
40
60
80
100
120
<10 >10 and <15 >150
20406080
100120140160180200
Female Male
THYROID CANCER IN CHILDRENSEX AND AGE AT DIAGNOSIS
other series
0%10%20%30%40%50%60%70%80%90%
100%
Poland Barcelona
MaleFemale
0%
10%
20%
30%
40%
50%
60%
<10 >10 and <15 >15
PolandBarcelona
0%
20%
40%
60%
80%
100%
Male 31% 35% 28% 38% 28% 35%Female 69% 65% 72% 62% 72% 65%
Poland England France / Italy Belarous Poland 07 Barcelona
< 15 years < 21 years < 21 years < 18 years < 18 years
THYROID CANCER IN CHILDRENSEX AND AGE AT DIAGNOSIS
different series
0%
20%
40%
60%
80%
100%
Follicular 29% 23% 17% 6% 18% 16%Papillar 71% 77% 83% 94% 82% 84%
Poland England France / Italy Belarous Poland 07 Barcelona
< 15 years < 21 years < 21 years < 18 years < 18 years
THYROID CANCER IN CHILDRENHISTOLOGYdifferent series
• papillary 84 %• follicular 16 %
THYROID CANCER IN CHILDRENHISTOLOGY
Vall Hebron series
16%
84%
02468
10121416
<5y 5-6y 7-8y 9-10y 11-12y 13-14y 15-16y 17-18y
PapillaryFollicular
• papillary: o lymph node involvement +++o lung metastases
• follicularo less lymph node involvemento fewer metastases
56% of patients showed advanced disease at the moment of diagnosis:
THYROID CANCER IN CHILDRENSTAGING AT DIAGNOSIS
– 63.7% lymph node involvement
– 22.5% pulmonary metastasisStage I-IIStage III-IV
CHILDREN ADULTSEXTRATHYROIDAL INVASION 24% 16% P 0,1NECK NODE INVOLVEMENT 90% 35% P 0,001DISTANT METASTASES 7% 2% P 0,001
Zimmerman, 1988Thompson, 2004
VH series
2003 - 2005
• Proven radiation: increase of thyroid cancer incidence in children and adolescents
• Data are compatible with experiences of the past after external exposure
• Projected number of cases for 50 years (Belarus) 15.000 • uncertainty range 5000 – 45.000• increase 80% above baseline
Demidchik, 2006
Center for THYROID TUMOURSMINSK 1986 – 2003
• 740 paediatric patients • Boys 279• Girls 461• Ratio 1 : 1,6
• Mean duration follow-up : 96,6 months (1,5 – 220)• 30 % (N=220) followed > 10 y• 80 % (N=599) followed > 5 y
THYROID CANCER in children and adolescentFrom Belarus after Chernobyl accident
Demidchick, 2003
Median latent interval: 13 yearsRange 6-30 years
Acharya, 2003Sigurdson, 2005
THYROID CANCER in children and adolescentFrom Belarus after Chernobyl accident
Dose and Relative Risk• Median latent interval: 13
years• Range 6-30 years
• Risk increases with radiation doses up to 20-29 Gy
• Risk decreases at radiation doses > 30 Gy
Twenty years' experience with post-Chernobyl thyroid cancerBest Pract Res Clin Endocrinol Metab
2008 22 (6): 1061-73
Children under the age of 1 at exposure show the highest susceptibility,
and carry this risk with them into adult life
Twenty years' experience with post-Chernobyl thyroid cancerBest Pract Res Clin Endocrinol Metab
2008 22 (6): 1061-73
• 4000 cases have been attributed to the accident, but so far very few have died. • The risk falls rapidly with increasing age at exposure.
THYROID CANCERSTAGING
• casual finding• cervical mass: increased cervical perimeter 92 %
• 68 % thyroid nodules• 25 % lymph nodes
• cervical lymph nodes40-80 %
• hoarness, dyspnea• lung metastasis
• miliary 97% - nodular 3%• almost always functional• may not be detected on chest Xray or CT• always detected on post 131I therapy scan
• rarely other metastasis
THYROID CANCER IN CHILDRENCLINICAL SYMPTOMS
Vassilopoulou, 1993Schlumberger, 1996
Ronga, 2004Bal, 2004
• casual finding• cervical mass: increased cervical perimeter 92 %
• 68 % thyroid nodules• 25 % lymph nodes
• cervical lymph nodes40-80 %
• hoarness, dyspnea• lung metastasis
• miliary 97% - nodular 3%• almos always functional• may not be detected on chest Xray or CT• always detected on post 131I therapy scan
• rarely other metastasis
THYROID CANCER IN CHILDRENCLINICAL SYMPTOMS
N Mean SD EE Stage 1 15 15,53 2,615 ,675 Stage 2 19 14,42 3,133 ,719 Stage 3 26 13,35 3,334 ,654 Stage 4 18 11,17 4,048 ,954 -
+p = 0.002
THYROID CANCER IN CHILDRENSTAGING AT DIAGNOSIS
VH series
INVERSE CORRELATION between:
• age at diagnosis• stage
0
5
10
15
20
25
30
Stage 1 Stage 2 Stage 3 Stage 4
MEAN AGEN
YOUNGER = HIGHER STAGE
0%10%20%30%40%50%60%70%
N1 58% 54% 65% 62% 65%M1 Stage IV 16% 17% 18% 13% 24%
Poland France / Italy Belarous Poland 07 Barcelona
THYROID CANCER IN CHILDRENSTAGING AT DIAGNOSIS
different series
THYROID CANCER IN CHILDRENCLINICAL SYMPTOMS
VH series
P = 0.008
increased cervical perimeter 87,5%thyroid nodule 65,0%
females 73,1%males 50,0%
lymph nodes 22,5%females 11,5%males 42,9%
increased cervical perimeter vs age< = 10 y 47,1%> 10 y 15,9%
P = 0.008
P = 0.024
CHILDREN adult scoring systems are not valid
THYROID CANCER IN CHILDRENPRONOSTIC FACTORS
CHILDREN AND ADOLESCENTSHAVE AN
EXCELLENT LONG TERM PROGNOSISWITH A
LOW MORTALITY RATEDESPITE EXTENSIVE DISEASE
WITH FREQUENT METASTATIC DISEASEAT PRESENTATION
AND HIGHER RECURRENCE RATE
Handkiewicz-JunakJ Nucl Med 2007; 48:879–888
THYROID CANCER IN CHILDRENPRONOSTIC FACTORS
TOTAL THYROIDECTOMY>>> less than total thyroidectomy
Intergroup difference:P < 0.00005Cox–Mantel test
THYROID CANCER IN CHILDRENPRONOSTIC FACTORS
RADIOIODINE TREATMENT>>> no radioiodine treatment
Intergroup difference:P < 0.0005Cox–Mantel test
Handkiewicz-JunakJ Nucl Med 2007; 48:879–888
NO LYMPH NODE METASTASES>>> lymph node metsor>>> status lymph nodes unknown
Intergroup difference:2 vs 3 P = 0.006 Cox–Mantel test
THYROID CANCER IN CHILDRENPRONOSTIC FACTORS
1=unknown2=LN neg3=LN pos
Handkiewicz-JunakJ Nucl Med 2007; 48:879–888
Multivariate analysis of prognostic factors for differentiatedthyroid carcinoma in children (EJNM, 2000)
THYROID CANCER IN CHILDRENPRONOSTIC FACTORSCox Regression Analysis
• echography with percutaneous aspirative punction
• thyroid scintigraphy• ressection of a cervical lymph node
differential diagnosis – lymphoma– tuberculosis– Epstein Barr virus– ricketsiosis
• abnormal thorax Xray : lung metastasis• metastasis: lung and lymph nodes
THYROID CANCER IN CHILDRENDIAGNOSIS
1 - SURGERY
2 - RADIOIODINE THERAPY3 - HORMONAL SUPPRESSIVE THERAPY
THYROID CANCER IN CHILDRENTREATMENT
4 - OTHERS: in some casesRADIOTHERAPY CHEMOTHERAPY
1 - SURGERY– Total (or near-total) thyroidectomy
– Frequent multifocality and bilaterality in papillary thyroid carcinoma
– Longer recurrence-free survival after total vs less than total thyroidectomy
– Lymphadenectomy: because frequent high staging or local involvement– Routine dissection of central neck compartment– Modified lateral neck dissection in case of proven latero-
cervical metastases– Avoid radical neck dissection
THYROID CANCER IN CHILDRENTREATMENT
Jarzab, 2000Thompson, 2004
Scheurmann, 1996
THYROID CANCER IN CHILDRENTREATMENT
1 - SURGERY
2 - RADIOIODINE THERAPY3 - HORMONAL SUPPRESSIVE THERAPY
4 - OTHERS: in some casesRADIOTHERAPY CHEMOTHERAPY
• FOLLOW-UP:– Serum thyroglobuline (Tg) level– Whole body scan (WBS)
• SURGERY– Total or near-total thyroidectomy
• THYROID TREATMENT:– ablative 131-Iodine therapy (mean individual dose of 10.27 GBq)
Free of diseaseTg < 2 ng/mLNegative WBS
THYROID CANCER IN CHILDRENTREATMENTVH series
• 26 (32.5%) patients
• Mean age: 12.4 ± 3.8 years
• Directly related with:– Advanced disease (p = 0.002)– Papillary pattern (p = 0.007)
THYROID CANCER IN CHILDRENSURGICAL COMPLICATIONS
VH series
Luster et al, 2009J Clin Endocrinol Metab 94: 3948 –3953
THYROID CANCER IN CHILDRENUse of rhTSH
TSH stimulation of rhTSH in children and adolescents• the approved adult dosage appears to be well-tolerated in thispopulation• seems to be clinical safety• reduced doses also may safely provide acceptable TSH stimulation
Paediatric rhTSH use to avoidhypothyroid morbidity
Old protocol with high ablative doses:• Doses: 50-100 mCi 131I/week during 3 weeks• WBS 4th day after every therapeutic dose• L-Thyroxin to suppress TSH levels • Whole-body scan (WBS): 5mCi 131I
HU VALL HEBRONPROCEDURE
Differenciated Thyroid Carcinoma
Current protocol with low ablative doses:• Single dose: 50-150 mCi 131I under rhTSH
• Children < 30 kg: 2 doses rhTSH 0,5• Children > 30 kg: same as adults
• 7th day after therapeutic dose• WBS• SPECT-CT: improvement
• L-Thyroxin to suppress TSH levels • Whole-body scan (WBS): 5mCi 123I under rhTSH
HU VALL HEBRONPROCEDURE
Differenciated Thyroid Carcinoma
WBS and Tg +
• Treatment 131Ior
• Surgery
Tg (rhTSH) > 1 ng/ml
WBS neg and Tg +
Lesion detection:• Doppler-US• MRI• PET under rhTSH
PAAF
• WBS / rhTSH • RCT + Tg
abnormalUS and/or thorax xR with Tg > 1 ng/ml
abnormalUS and/or thorax xR with Tg < 1 ng/ml
P = NS
Old protocolCurrent protocol
VALL HEBRON SERIESFOLLOW-UP
Differences between both protocols
No significant differences between both protocols
Follow-up (years)
PROTOCOLAGEMean
SEXfemale%
HISTOLOGYpapillary%
Advanced StageIII-IV
DOSEMean
high dose 12,7 ±4 63,00% 96,60% 55,00% 402±281low dose 14,7 ±3 72,00% 77,77% 58,33% 174±102Significance NS NS NS NS p < 0,001
All mets located in the lung123I WBS
131I post-treatment WBS
THYROID CANCER IN CHILDRENVH series
METASTASIS
LUNG METASTASIS 23,8%initial stage 22,5%recurrence 1,2%
Papillary 94,7%
THYROID CANCER IN CHILDRENVH series
LONG TERM FOLLOW-UP
FOLLOW-UP > 2 y 87,5%MEAN 10,8 yRANGE 2 y - 24 y
free of disease persistent diseaseFIRST CONTROL
6 months 36,2% 63,8%
END FOLLOW-UP 87,2% 12,9%
RECURRENCES 10,0%local 85,7%lung mets 14,3%
THYROID CANCER IN CHILDRENVH series
LONG TERM FOLLOW-UP
Persistent disease Disease Free SignificanceMEAN AGE 11,1 ±3,2 14 ±3,5 NS
Persistent disease Disease Free SignificanceMEAN AGE 11,1 ±3,2 14 ±3,5 NS
Persistent disease Disease Free Significancenumber (f/m) 4/4 43/17
% females 50,00% 71,00% NSSEXPersistent disease Disease Free Significance
number (f/m) 4/4 43/17% females 50,00% 71,00% NSSEX
Persistent disease Disease Free SignificancePAPILLAR HISTOLOGY number 8 54
% 100,00% 85,00% NSPersistent disease Disease Free Significance
PAPILLAR HISTOLOGY number 8 54% 100,00% 85,00% NS
SEX 0,143AGE 0,143
HISTOLOGY 0,584
P
THYROID CANCER IN CHILDRENVH series
LONG TERM FOLLOW-UP
p = 0.014
13 0 13100,0% ,0% 100,0%21,7% ,0% 18,8%18,8% ,0% 18,8%
16 1 1794,1% 5,9% 100,0%26,7% 11,1% 24,6%23,2% 1,4% 24,6%
21 2 2391,3% 8,7% 100,0%35,0% 22,2% 33,3%30,4% 2,9% 33,3%
10 6 1662,5% 37,5% 100,0%16,7% 66,7% 23,2%14,5% 8,7% 23,2%
60 9 6987,0% 13,0% 100,0%100,0% 100,0% 100,0%87,0% 13,0% 100,0%
Recount% pretreatmentstage% end follow-up% totalRecount% pretreatmentstage% end follow-up% totalRecount% pretreatmentstage% end follow-up% totalRecount% pretreatmentstage% end follow-up% totalRecount% pretreatmentstage% end follow-up% total
Stage 1
Stage 2
Stage 3
Stage 4
preTreatmentstage
Total
Free ofdisease
Persistentdisease
End follow-up
Total
Initial Stage vs Status at the end of follow-up:
THYROID CANCER IN CHILDRENVH series
LONG TERM FOLLOW-UP
Stage I Stage II Stage III Stage IV Totalnumber 0 1 1 6 8
% 0,00% 5,50% 4,35% 42,85% 11,90%number 12 17 22 8 59
% 100,00% 94,50% 95,65% 57,15% 88,10%number 12 18 23 14 67
% 100,00% 100,00% 100,00% 100,00% 100,00%
Persistent diseaseDisease Free
Total
P = 0.003
VALL HEBRON SERIESFOLLOW-UP
Predictive Factors: STAGING
Stage I-II-III Stage IV Totalnumber 2 6 8
% 3,80% 42,85% 11,90%number 51 8 59
% 96,20% 57,15% 88,10%number 53 14 67
% 100,00% 100,00% 100,00%
Persistent diseaseDisease
Free
TotalP = 0.001
VALL HEBRON SERIESFOLLOW-UP
Predictive Factors: STAGING
p = 0.009
28 0 28100,0% ,0% 100,0%46,7% ,0% 40,6%40,6% ,0% 40,6%
32 9 4178,0% 22,0% 100,0%53,3% 100,0% 59,4%46,4% 13,0% 59,4%
60 9 6987,0% 13,0% 100,0%100,0% 100,0% 100,0%87,0% 13,0% 100,0%
Recount% TG at 6 month% end follow-up% totalRecount% TG at 6 month% end follow-up% totalRecount% TG at 6 month % end follow-up% total
Negative
Positive
TG (6 month)
Total
Free of diseasePersistentdisease
End of follow-up
Total
THYROID CANCER IN CHILDRENLONG TERM FOLLOW-UP
• Tg 6 month – status at the end of follow-up:
p = 0.214
Tabla de contingencia
24 4 2885,7% 14,3% 100,0%38,1% 66,7% 40,6%34,8% 5,8% 40,6%
39 2 4195,1% 4,9% 100,0%61,9% 33,3% 59,4%56,5% 2,9% 59,4%
63 6 6991,3% 8,7% 100,0%100,0% 100,0% 100,0%91,3% 8,7% 100,0%
Recount% TG at 6 month% of Recurrence% totalRecount% TG at 6 month% of Recurrence% totalRecount% TG at 6 month% of Recurrence% total
Negative
Positive
TG 6 month
Total
0 1Recurrence
Total
THYROID CANCER IN CHILDRENLONG TERM FOLLOW-UP
123I- WB scanPost-surgery before treatment
131I- WB scan7 days after treatment
• Low prevalence• Neck irradiation: predisposing factor
IN SUMMARYTHYROID CANCER IN CHILDREN
• The DTC is frequently associated with the presence of lymph nodes and distant metastasis (lung) at the moment of diagnosis
• Recommendation:– Total or nearly total thyroidectomy – Central neck dissection – 131I ablation– hormonal suppressive therapy
IN SUMMARYTHYROID CANCER IN CHILDREN
• Relative mortality is very low– Despite initial advanced disease– Frequent recurrences
• Overall rather good prognosis
IN SUMMARYTHYROID CANCER IN CHILDREN
• In children, the follicular type tends to be less agressive than the papillary
IN SUMMARYTHYROID CANCER IN CHILDREN
• The initial stage IV is a bad prognosis factor
IN SUMMARYTHYROID CANCER IN CHILDREN
• A Tg value < 2 ng/mL measured postreatment (6 month) is a good prognosis factor due its association to:– High rate of completely remission at the end of follow-up– Low rate of recurrences
THANK YOU VERY MUCH FOR YOUR
ATTENTION!