roca thyroid cancer children eng -...

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!