THYROID CANCER EVOLUTION OF THE DISEASE EVALUATED IN ONE SETTING VOICHIŢA MOGOŞ 1. EUGEN...

THYROID CANCEREVOLUTION OF THE DISEASE EVALUATED IN

ONE SETTING

VOICHIŢA MOGOŞ1. EUGEN TIRCOVEANU2

1. Clinic of Endocrinology, 1st Surgery Clinici University of Medicine and Pharmacy “Gr.T Popa” Iasi

Histological profile of thyroid cancer between 1975-2009.Chernobyl effect and

universal iodine fortification of salt

PURPOSE

To evaluate the evolution in time of incidence, clinical and histological profile in our setting from 1975 to 2009 taking into account two main events:

• The accident from Chernobyl

• The role of iodine prophylaxis

Data from literature

• There was noticed a steady increase of thyroid cancer all over the world

• External irradiation in the only well documented cause in papillary thyroid cancer leading to RET/PTC re-arrangements

• Iodine deficiency may play a role in the development of follicular cancer and may favor the development of anaplastic carcinoma

• Iodine repletion is associated with increased incidence of papillary carcinoma with excellent prognosis

There was noticed a steady increase of thyroid cancer all over the world

Davies L et al. JAMA 2006, 295, 2164-2167

Between 1973-2002:• 2.4 times increase in thyroid cancer incidence• All thyroid cancer: 3.6/105 to 8.7/105/year (with 5.1/105)• Papillary cancer: 2.7/105 to 7.7/105/year • Small papillary cancer account for 87 % of the cancer • Mortality decreased from 0.57 to 0.47/105/year

– External irradiation stopped after 1961

– Most data show that precocious diagnosis by ultrasound and FNB leads to increased incidence but stable mortality

– Papillary cancer has a long evolution and excellent survival

– Over diagnosis increased the number of radical surgery and its complications

Davies L., Welch HG.JAMA 2006,295, 2164-2167


Schottenfeld D et al. CA Cancer J.Clin. 1978, 28, 66-86 USA:Connecticut Tumor registry• 1949-1969: 1.4/105/year to 1970-1983: 4/105/year

– Papillary: 64 %– Follicular: 18 %– Medullary: 3 %

• New York a study on autopsies:– 16.4 /1000 all study– 19.6/1000 in women– 10.4/1000 in men

• Microcarcinomas:– USA: 1- 5.7 %– Japan: 17.9-24%


Scheiden P.et al. BMC Cancer 2006, 6, 102-109Evaluation in an European country – Luxembourg 30 years after Chernobyl in 2

cohorts: 1990-1994 (a) and 1995-1999 (b)• 310 new cases out of which 124 microcarcinomas < 1cm. After 1997• Increased microcarcinomas from 7 % to 16.6 %

– 46.5 % papillary– 13.3 % follicular– 27.3 % medullary

• Increased incidence from 6.4 to 8.6/105/year• Increased incidence in women from 7.4 to 10.1/105/year• Increased incidence in men from 2.3 to 3.6 /105/year

Mahoney MC et al. Int.Epidemiol. 2005, 34, 714-722 (1970-2001)• Severe exposure: increase incidence in males + 775%, in females:+1925%• Low exposure: increased incidence in males:+54 %, in females: + 250 %

Scheider R et al. BMC Cancer 2006, 6, 102-116Luxembourg


Leehardt L et al. Thyroid 2004, 14, 1056-1060• FRANCE: 1998-2001• Increased incidence of thyroid cancer• Increased prevalence of cancer operated among thyroid

nodules submitted to surgery due to • increased assessment with ultrasound from 3 to 84 5• Increased assessment through FNB from 8 to 36 %

• In France there was notice no association between cancer incidence and nuclear accident from Chernobyl


Reynolds RM et al. Clin.Endocrinol. (Oxf) 2005, 62, 156-162

Scotish Cancer Registry 1960-2000:• Incresed incidence of thyroid cancer from 1.76 to 3.54/105/year

in women• Increased incidence from 0.82 to 1.25/105/year in men• Decreased mortality from 1.05 to 0.28 % in women and from

0.73 to 0.34 in men• Decreased follicular cancer• Stable incidence of medullary carcinoma• Increased survival

External irradiation was the only well documented cause in papillary thyroid cancer leading to RET/PTC re-arrangements

Data from internal irradiation are related to the best studied nuclear plant accident from Chernobyl

Thyroid irradiationThe role of external irradiation in induction of thyroid cancer was

first noticed by Duffy and Fitzgerald in 1953, in those who received external irradiation for different diseases. 36 % of children who developed thyroid cancer had neck irradiation in their personal history

The role of radioiodine was largely studied after Chernobyl Contamination:

• Internal irradiation by inhalation or ingestion of: radioactive iodine 131I, 132I, 135I, 131mTe (tellurium). 133 Te

• External irradiation X ray, gamma Irradiation due to radioactive material deposits on the ground1

• Belarus: cancer in children: 1/106 before and 100/106 after Chernobyl2. The risk in children less than 1 year is 30 fold greater3

Cardis E et al. J.Natl.Cancer Inst. 2005, 97, 724-732Nagatachi S et al. Thyroid 2002, 12, 899-896Boltze C et al. Oncology 2009, 22, 459-467

Thyroid irradiation

Questions: • Which is the role of the previous iodine intake in the

contaminated area• Which are the factors that modify the risk of thyroid cancer

after exposure to irradiation: – contamination level

– individual factors

Total dose of exposure:

– 365 mGy in Belarus (7- 3109 mGy)

– 40 mGy Rusian Federation (max. 10.2Gy)

– Dose of exposure to radioiodine: 1-2 mGy

Cardis E et al. J.Natl.Cancer Inst. 2005, 97, 724-732

Thyroid irradiation

• The risk to develop thyroid cancer after irradiation in individual who previously consumed stable iodine after an exposure to 1 Gy is reduced 5 fold

• Low level of iodine in the soil is correlated with a 3 fold increase of risk to develop cancer compared with residents in areas with naturally more iodine in soil

• At doses of contamination between 1.5-2 Gy there is no linear correlation between exposure and risk of cancer

• Previously ingestion of iodine reduces radioactive iodine intake• Increased iodine supply reduces thyroid volume and

multiplication of thyroid cell and risk of occurrence of mutations


Cardis E et al. J.Natl.Cancer Inst.2005, 97, 724-732

Thyroid irradiation

Pacini F. et al. J.Clin.Endocrinol.Metab. 1997, 82, 3563-3569Greenspan FS JAMA 1977, 237, 2089-2091

1986-1995 in Bellarus 472 patients among which 97.7 were differentiated cancers

• median age: les than 14 years

• median age at exposure: 4.4 in children and 8.9 in adolescents

Italy and France after Chernobyl: 369 patients

Mean age in children more than 14 years

Follicular cancer: 15.2 % compared with 5.3 % in Bellarus

Most effected children were exposed at less than 5 years1

Most cancers occur 5-30 years after irradiation but the risk last to 50 years2

Thyroid irradiation

1. Pacini F. et al. J.Clin.Endocrinol.Metab. 1997, 82, 3563-35692. Tuttle RM et al. Clin.Oncolocy 2011, 23, 268-275

Differences among cancers developed after Chernobyl and those developed in Italy1

• Extrathyroidal extension: 49.1% vs 24.9 %

• Lymph node involvement: 64% vs 53.9 %

• Distant metastasis: 7.8 % vs 17.3 %

• For more latent forms of papillary cancer a new pick of incidence may be expected

20 years after Chernobyl accident 5000 cases of thyroid cancer were diagnosed. 60-70 % had N1 and 10-15 had M12

Relationship between the degree of iodine contamination and number and percentage of new cases of thyroid cancer in children and adolescents after Chernobyl nuclear reactor accident

Pacini F et al. J.clin.Endocrinol.Metab. 1997, 82, 3563-3569

Pacini F et al. J.clin.Endocrinol.Metab. 1997, 82, 3563-3569

Iodine deficiency may play a role in the development of follicular cancer and may favor the development of anaplastic carcinoma

Iodine and thyroid cancer• The relationship between thyroid cancer and dietary iodine is

controversial• There are some data that could demonstrate that iodine deficiency

may increase thyroid cancer in some areas• Iodine may act as adjuvant factor for carcinogensis and may have a

role in the hystological profile of thyroid cancer• Is obvious from all statistics that increased dietary iodine is

associated with an increase of incidence of thyroid cancer1

• Sicilia: – Thyroid malignancies: IDA – 2.96%, ISA 5.48 %

– Follicular cancer: IDA; up to 127/105,

– Anaplastic cancer: 93/1051. Knobel M et al. Arq.Bras. Endocrinol.Metab. 2007, 51, 701-712

2. Belfiore A et al. Cancer 1987, 60, 3096-3192

Iodine and thyroid cancer

Iodine deficiency is associated with a relative risk (RR) of cancer as follows (Sweden)1

• 0.92 for all histological types• 0.80 for papillary cancer • 0.87 for anaplastic carcinma• 1.98 for follicular cancer

The risk for follicular cancer is 1.3-15 in iodine deficient areas and depends of the time of residence in these areas2

1. Petterson B et al. Int.J.Cancer 1996, 65, 13-19

2. Galanti MR et al. Int J.Cancer 1995, 61, 615-621


Frequency of thyroid cancer by tumor type in Salta, Argentina before and after iodine prophylaxis

Total number of cases Years after iodine prophylaxis

10 years 11-26

59 85

Papillary 26 46

Follicular 15 15

Anaplastic 9 13

Ratio between Papillary and follicular cancer

1.7 3.1

Harach C et al. Clin.Endocrinol. 1995, 61, 615-621


Histologic pattern of thyroid tumors in two areas of Sicily, Italy with low and adequate iodine intake

Total number of cases submitted to surgery

Low intake High intake

911 (126) 2437 (419)

Papillary 11 103

Follicular 11 27

Anaplastic 5 9

Belfiore A et al. Cancer 1987, 60, 3096-3102

Iodine prophylaxis and thyroid cancer

Incidence of different forms of thyroid cancer before and after iodine prophylaxis

Papillary: pre prophylaxis 44% vs post prophylaxis: 60 %

Papillary/follicular ratio: 1.7/1 to 3.1/1 1

Ratio papillary to follicular cancer according to iodine intake2

IDA: 0.1/1, moderate intake: 1.6/1-3.7/1, high intake: 3.4/1-6.5/1

1986-1999: 1500 new cases:

Incidence: 3.86 to 6.08/105

After prophylaxis: papillary to follicular ratio: 5.323

1. Harach H et al. Endocr.Pathiol. 2002, 13, 175-181

2. Lind p et al. Thyroid 1998, 8, 1179-1183

3. Szybinski Z et al. Wiad Lek 2001, 54, 106-116


Incidence of different forms of thyroid cancer before and after iodine prophylaxis 1974-1976 and 1992-1994

• Increased percentage of thyroid cancer on thyroidectomies• Papillary: 54.3 %• Follicular: 27 %• Anaplastic: 11.1 %• Medullary: 4.6 %

Papillary to follicular ratio:

1974-1976: 0.60

1992-1994: 6.88

Deandrea M et al. J.Endocriol.Invest. 1997, 20, 52-58


iodine prophylaxis:• Increased incidence of papillary cancer• Decreased incidence of follicular cancer• Decreased incidence of anaplastic cancer• Improved prognosis

Bakiri et all.Cancer 1998, 82, 1146-1153

Histology of thyroid cancer in iodine deficient areas (Algeria)

Improvement of socio-econimc status from 1966-1981 and 1982-1991

Bakiri et all.Cancer 1998, 82, 1146-1153

Schottenfeld D, Gersman ST. Epidemiology of thyroid Cancer 2008

Histological profile of thyroid cancers in an iodine sufficient area ( Connecticut - USA )

Burges JR et al.J.Clin. Endocrinol.Metab.2000, 85, 4, 1513-1517

There is a trend to increase the incidence of thyroid cancer as well as an increase of papillary thyroid cancer

Histology and age are the best predictor factors for survival

Scheiden P et al.BMC Cancer 2006, 6, 102-106

5 years survival:

• Papillary: 96 %

• Follicular: 88.9 %

• Medullary: 90.9 %

Hundahl Sa et al. Cancer 1998, 83, 2638-2648

10 years survival:

• Papillary: 93 %

• Follicular: 85 %

• Hurthle cell: 76 %

• Medullary: 75 %

• Anaplastic: 14 %

Passler G et all.Endocrine-Related Cancer 2004,11, 131-139

Histology and age are the best predictor factors for survival

Radioactive elements release after CHERNOBYL 1986

CONTAMINAREA RADIOACTIVA DUPA CERNOBIL 1986 - ROMANIA

What happened in Romania? It partially remains in the area of suppositions

RET/PTC in the key mutation seen in radiation-induced thyroid cancer and activation of BRAF is associated with sporadic forms of differentiated thyroid carcinoma

Xing s et al Endocrine reviews 2007, 28, 742-762

Data from literature

• Elisei has demonstrated that clinical and histological profile of thyroid cancers was modified during the last 35 years through:

• Increased incidence of papillary cancers from 80,5 % to 91% during these years

• Decreased follicular cancers from 19,5 % to 9 %; • Increased incidence of cancer with diameter of less than 1 cm. from

7,9% in the firs half of the interval to 28,7 % in the second• Reduced incidence of macro-invasive cancers from 7 % to 1,9 %;• Reduced incidence of cancers with distant metastases from 5,4 la 2

%;• Reduced incidence of cases with lymph node metastases from 34,2

% to 22, 4%;• Reduced incidence of cases in advanced stages according to TNM

VI, for stage III 10,8 to 7,4 % and for stage IV from 4,2% to 1,7 %.

Elisei R., et all.J.Clin. Endocrinol.Metab. 2010,

MATHERIAL AND METHOD

• Data from files of patients with thyroid tumors submitted to surgery between 1975-2009 (35 years) were divided into 5 years intervals and analyzed for:

• New cases for each interval• Histology• Clinical appearance • Stage of the disease according to TNM classification and

tumor stage grouping TNM VI• Ratio between papillary and follicular cancer as indirect

signs for the role of supposed external irradiation and modification due to iodine prophylaxis

MATHERIAL AND METHOD

• From 1981 most patients were assessed based on fine needle biopsy performed within the Department of Endocrinology of our hospital

• Our data were compared with data from the Department of Endocrinology analyzed between 1971 and 2000 for patients admitted in this setting including those operated in other surgery clinics

Algorithm of diagnosis for thyroid nodules used after 1981 in the

Clinic of Endocriology IASI

THYROID NODULE

ULTRASOUND CYST SOLID OR MIXED LESSION

FNB

MALIGNFOLLICULAR NEOPLASM

SCINITIGRAPHY

COLDWARM

LOW RISK HIGH RISK

THIROIDECTOMY

FOLLOW-UP

ABC

BENIGN

T4

EVACUAATION,

SCLEROZING

RECURRENCE

SOLVED

E.Zbranca et.al.Symp.Nat.Endocrinol.1995, Endocrinologie Clinica 1997

EPIDEMIOLOGICAL BACKGROUND

Moldova is situated in the northern part of Romania

Different studies provided data that show a decrease of prevalence of goiter and a mild to moderate iodine deficiency assessed by urinary iodine determination, except for same areas where urinary iodine is still low

Urinary Goiter %

COUNTY Iodine g/dL

1975 1986 1999Thyroid

ultrasound examination

Suceava 6.55 60 30.4 31.8Botosani 8.62 30.7 16.1Neamt <5 53.7 22.2 23.4Iasi 9.93 33.3 24.7 6.4

Interval Number of cases

Age Females Males

1975 - 1979 19 45.7 ± 10.9 18 1

1980 - 1984 18 52.9 ± 14.9 15 3

1985 - 1989 17 49.5 ± 15.6 13 4

1990 - 1994 37 48.6 ± 16.8 32 5

1995 - 1999 52 51.5 ± 15.8 43 9

2000 -2004 71 53.1 ± 15 53 18

2005-2009 131 51.8 ± 14.2 109 22

1975 - 2009 345 51.3 ± 14.8 283 62

Demographic data of patients with thyroid tumors admitted in the Ist Surgery Clinic of Iasi

RESULTS: thyroid tumors submitted to surgery between 1975-2009 in the 1st Surgery Clinic of Iasi-

345 cases

19 18 1737

5271

131

02040

6080

100120

140

1975-79

1980-84

1985-89

1990-94

1995-99

2000-05

2005-09

interval

Mumber of thyroid tumors operated between 1975-2009

5.5 5.2 4.910.72 15.1

20.57

37.97

0

20

40

60

80

100

120

140

1975-79 1980-84 1985-89 1990-94 1995-99 2000-05 2005-09

New cases of thyroid tumors operated for each 5 years interval in the 1st Surgery clinic of Iasi

Nr.of tumors

%

WHAY WE FOCUSED OUR RESEARCH ON CHANGES OF HYSTOLOGICAL PROFILE OF

TUMORS DURING TIME?

• Histology, age and stage at diagnosis are the best predictive prognostic factors for thyroid cancers

• All these factors are influenced by at least two major events that happen in Romania:

• Hypothetical external irradiation after Chernobyl with increase of papillary forms

• Important modification of iodine supply due to active and universal salt iodination also with increase of papillary form and decrease of incidence of goiter that may mask a carcinoma

Survival in thyroid cancers acording to histology Clinic of Endocirnology Iasi 1993

0

20

40

60

80

100

120

0 5 years 10 years 15 years

Papillary

Follicular

Medullary

Anaplastic

Survival in thyroid cancers acording to age at diagnosis

Clinic of Endocrinology Iasi

0

20

40

60

80

100

120


<45 years

> 45 years

Survival in thyroid cancers acording to tumor staging

Clinic of Endocirnology Iasi

0

20

40

60

80

100

120


Stage I

Stage II

Stage III

Stage IV

Histological profile of thyroid cancers Ist Surgery Clinic Iasi

194

17

62

23

14

14

21

56.23

4.92

17.97

6.66

4.05

4.05

6.08

0 50 100 150 200 250

Papill

Pap/Foll

Foll

Foll less dif

MTC

Anaplasic

Other %

Nr.of cases

Cancers derived from follicular epithelium (1st.Surgery Clinic)

59.9

5.24

19.13

7.09

4.32

4.32

100

0 50 100 150 200 250 300 350

Papillary

Papil/foll

Follicular

Foll less dif

MTC

Anaplasic

All

%

Nr.of cases

Taking into account only cancers derived from follicular epithelium the percentage of papillary and follicular cancers in more obvious among al

tumors

25.56

23.62

14.88

15.21

6.14

8.7

5.82

0 5 10 15 20 25 30

Papilary

Pap/fol

Follicular

Foll less dif

MTC

Anaplastic

Others

Histological profile of thyroid tumors in the Clinic of Endocrinology of Iasi % 1975 - 2000

Expectation after external irradiation and improved iodine supply

• Increased incidence of papillary carcinomas in younger age, but the risk after exposure persists long life after exposure

• Increased incidence of aggressive forms in children and young adult immediately after irradiation

• Normal iodine intake is associated also with increase of papillary cancers with good prognosis even in advanced forms and increased papillary to follicular ratio

• Decrease incidence of follicular cancer with a less good prognosis

• Decrease incidence of anaplastic carcinoma• Diagnosis made in less advanced stages of the disease

Interval1975-1979

1980-1984

1985-1989

1990-1994

1995-1999

2000-2004

2005-2009

Papillary 21.05 33.3 23.5 21.6 30.76 61.97 85.5

Pap/fol 11.1 11.7 2.7 17.3 2.8 0.8

Follicular 63.2 44.5 23.5 35.13 25 9.85 3.81

Foll less dif. 19.5 11.1 29.4 27.02 5.76 1.4

MTC 5.26 3.84 5.6 3.8

Anaplastic 11.76 13.5 1.92 9.85 1.52

Striking features noticed during the analyzed interval: increase incidence of papillary cancers, decrease of follicular forms, decrease of anaplastic carcinomas – all seems to be related with a better iodine prophylaxis and perhaps to external irradiation due to Tchernobil accident

Clinical data of thyroid cancers 1st Surgery Clinic

0 10 20 30 40 50 60 70 80

Papill

Pap/fol

Follicular

Foll less dif

MTC

Anaplastic

Others

MNG+Lymph node

MNG

Sol.Nod+ Lymph node

Solitary nodule

12

29

46

87

55

80

0 20 40 60 80 100

1971-75

76-80

81-85

86-90

91-95

96-2000

NEW CASES OF THYROID CANCER 1971 – 2000CLINIC OF ENDOCRINOLOGY IASI

0

10

20

30

40

50

60

70

solitary.nod SN+lymphnode MNG MNG+L DM Bmet

papillary

follicular

mixt/pna

anaplastic

medullary

Interval1975-1979

1980-1984

1985-1989

1990-1994

1995-1999

2000-2005

2005-2009

Unilateral tumor 63.15 94.4 88.23 86.48 86.5 94.4 89.3

Bilateral tumor 36.7 5.6 5.88 13.5 13.4 5.63 10.6

Lymph node involvement 26.3 5.5 35.3 72 42.3 31 22.9

Developedon goiter 52.6 55.5 47.05 71.8 74.46 83 16.7

The trend of thyroid cancer derived from follicular epithelium during 35 years is a slightly reduce of tumors diagnosed in later stages : bilateral, with lymph node involvement. Only in the last 5 years the histology did not reveal surroundings of goiter in the proximity of tumors due to active iodine prophylaxis

Interval1975-1979

1980-1984

1985-1989

1990-1994

1995-1999

2000-2004

2005-2009

micro carcinoma 5.4 4.5 6.25 0.8

T I 31.6 27.8 5.88 18.9 20.45 35.93 34.44

T II 57.9 55.5 58.8 32.4 43.2 26.6 25.6

T III 10.5 16.7 23.5 27.2 29.5 18.8 32.8

T IV 11.76 13.5 2.27 12.5 6.4

Tumor staging at time of diagnosis show that after 1990 there were discovered microcarcinomas, stage I tumors increase and stage IV tumors obviously decrease (TNM classification VI)

Interval1975-1979

1980-1984

1985-1989

1990-1994

1995-1999

2000-2004

2005-2009

TI 52.7 44.4 29.4 51.35 43.18 48.43 53.6

T II 47.36 44.4 35.3 24.32 27.3 18.75 24

T III 11.2 23.5 10.8 27.3 26.56 20.8

T IV 11.7 13.51 2.2 6.25 1.6

Grouping of tumor stage according to histology, tumor extension and age at diagnosis show that after 1990 slightly more tumors were discovered in less advanced stages even through the mean age at diagnosis does not change during the analyzed interval (TNM classification VI)

0.73 0.8 0.66 0.39 1.56

5.75

22.6

0

5

10

15

20

25

1975-79 1980-84 1985-89 1990-94 1995-99 2000-04 2005-09

Papillary to follicular ratio an indirect marker of iodine deficiency 1st Surgery Clinic

Pap/foll ratio

42.1

47.36

10.52

53.8

18.5

11.715.9

62

25.2

8.6

3.4

0

10

20

30

40

50

60

70

1971-1980 1981-1990 1991-2000

Changen in percentage of different forms of thyroid cancers derived of follicular cells 1975-2000

Clinic of Endocrinology IasiPapillary

Follicular

MixedFPA

Anaplastic

EVOLUTION of RATIO BETWEEN PAPILLARY AND FOLLICULAR CANCER

1971 – 2000Clinic of Endocrinology Iasi (309 cases)

1

2.21

3.5

1.86

3.14

0

0.5

1

1.5

2

2.5

3

3.5

<1980 1981-85 1986-90 1991-95 1996-2000

Lind P. 1998: this ratio depends of iodine supply

6,5/1 - 3,8 /1: increased iodine supply;

3,7/1 - 1,6/1: moderate iodine supply

1,6/1 - 1,19/1 iodine deficiency

The ratio between papilary and follicular cancer according to iodine supply in the studied area compared with other reported data*Deandrea 1997, ** Lind

1998

1.41.78

0.6

6.88

0.19

1.6

3.42.9

1.7

3.7

6.5

0.88

2.48

0

1

2

3

4

5

6

7

8

1971-1980

1981-1990

1991-2000

CONCLUSIONSOur data on patients with thyroid cancers analyzed over a period

of 35 years indicate that: • It is an important increase in each 5 years interval, of number

of new cases• There is an important increase of papillary cancer and the ratio

between papillary and follicular cancer and a decrease of anaplastic carcinoma

• There is increase of cases discovered in earlier stages of the disease

• We cannot assume that this events are due to the external irradiation because of lack of genetic and clinical evidence

• We believe that the afore mentioned evolution of histological profile of thyroid cancer in our setting is due to a better iodine prophylaxis

THYROID CANCER EVOLUTION OF THE DISEASE EVALUATED IN ONE SETTING VOICHIŢA MOGOŞ 1. EUGEN...

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