THYROITISDefinition: inflammatory diseases of the thyroid gland with different etiologic,

biologic, histologic and clinical aspects CLASSIFICATION

• ACUTE: bacterial, viral • SUBACUTE: de Quervain’s thryoiditis• CHRONIC:

• chronic autoimmune thyroidits• Tuberculous• Mycotic• Riedel’s thyroidits

ACUTE BACTERIAL THYROIDITISSigns and symptoms

• Fever • Pain profound and severe • Dysfagy - 90 % din cazuri• Dyspnea – 50 %• spasmodic cough

Laboratory data • increased ESR• leukocytosis with neutrophilia • Ultrasound: small or large hypoechoic areas• FNB: isolation of germs

Treatment : antibiotics or surgery if an abscess is formed

SUBACUTE ”DE QUERVAIN’S” THYROIDITIS

Sex ratio F/M: 3,6/1 – 10,6 /11 caz TS for 5 cases of Graves disease and for 20 cases of AIT

• 0,01 % of all hospitalized patients • 1,89 % of all patiens hospitalized for thyroid diseases • 9,9 % of subjects presenting with thyrotoxicosis • 1,52 % of patients investigated by FNB

ETIOLOGY• probably the disease is a response to a viral infection

GENETICS• those with HLA-Bw35 have a risk to develop the disease of 8-56.6 %• HLA-Bw35 allows the development of clinical symptoms • it has no relationship with the evolution of the disease

PATOGENICITY• interleukine 6 produced by monocytes si macrophages determine inflammation

• interleukine 2 +TNF a + interferon a determine destructive thyroiditis in 10 % of cases

• VEGF, basic FGF, PDGF determine granulomatous reaction• EGF determines by mitogenic effect the regeneration of the follicles

PATHOLOGY • Follicular disruption with thyroglobulin liberation is responsible for the initial

phase of thyrotoxicosis • granuloma:

• a center of giant cells surrounded by macrophages • epithelial cells surrounded by a crown of macrophages involved with

antigen presentation

Clinical signs and symptomsClassical

formNon classical form

History of viral infectionPainful thyroid Fever DysfagyPainful thyroid enlargement

Pain irradiates to the earsSimptoms of thyrotoxicosisMalaise

1 / 390 %90 %

90 %50 %

76 %

18 %

42 %

Laboratory data Imagery

Important increase of ESR Leukocytosis FT4 si FT3 increasedSuppressed TSH Increased thyroglobulin Transitory increased antithyroid antibodiesHLA-Bw 35+

Hipoechogenicity generalized or disseminated points Localized hipoechogenicityAbsent Tc 99 m uptakeReduced iodine uptake on scintigram67 Gallium citrat: scintiscan

Differential diagnosis Evolution and complications

Cyst with intracystic hemorrhage Tirotoxicosis induced by iodine loading (amiodarone)Thyroid cancer: FNB

Painless forms

Transient hypothyroidism second phase of evolution Recurrent disease is unpredictable Definitive recovery with euthyroidismDefinitive hypothyroidism <1/10

SUBACUTE THYROIDITIS – TREATMENT FORME SEVERE:GLUCOCORTICODS:

• Prednisone: 30-40 mg / day at the beginning of the disease with further reduction of the dosage

• Dexametazone: 3-4 mg /zi

MILD FORMS:Nonsteroid anti inflammatory drugs

TUBERCULOUS THYROIDITIS Is a very rare disease. Its clinical manifestation may be as a form of milliary

tuberculosis or in most of cases as a form of thyroid nodule. Thyroid ultrasound shows usually a thyroid nodule with internal necrosis. The only way to make a certain diagnosis is the fine needle biopsy with identification of BK on smears and culture of BK on specific medium.

AUTOIMMUNE THYROIDITISINCIDENCEAs most of autoimmune diseases autoimmune thyroiditis occurs most frequently

in women with a sex ratio between women and men of 1.5/1 or more.• 3,5 – 4,5 % of population present autoimmune thyroid diseases• 4,6 % of women and 1,23 %of men have antithyroid antibodies • 15 % of women over 60 years • lymphocytic infiltrations: 6,8 5 of women and 2,7 % of men • 50 % of those with antithyroid antibodies have TSH > 6 mU.I./ml• 60 % of those with TSH > 6 mU.I./ml have anti thyroid antibodies • 80 % of those with TSH > 10 6 mU.I./ml have anti thyroid antibodies • 5 % of those with TSH > 6 mU.I./ml develop overt hypothyroidism each year

PATOGENY• genetic predisposition • Viral aggression that determine liberation of thyroglobulin and other components

of thyroid cells into circulation leading to antibody formation

• excessive iodine supply leading to over iodinated thyroglobulin which becomes antigenic GENETIC PREDISPOSITION is confirmed by the following facts:

• affected individuals have relatives with autoimmune thyroid diseases • the disease occurs in individual with type DR3 and DR5 HLA which play the

most important role in antigen presentation to immune system by macrophages• it occurs in patients with genetic abnormalities :Turner, Klinefelter, Down

syndrome• it occurs frequently in association with other autoimmune diseases:• multiple autoimune endocrine diseases type I and II (type 1 diabetes mellitus,

adrenal failure, ovarian failure with precocious menopause), autoimmune hypophysitis Biermer disease , Sjogren’s syndrome, systemic lupus eritematosus, rheumatoid arthritis , miastenia gravis, interstitial lung disease,

• HLA-DR3 si HLA-DR4

ANTIBODIES THIROIDITIS and other diseasesANTI-TPO (PEROXIDASE) Hashimoto’s thyroiditis, Post partum

thyroiditisANTI – Tg Ab Hashimoto’s thyroiditisTSH -receptor stimulating antibodies HashitoxicosisTGI – thyroid growth immunoglobulins Hashimoto’s thyroiditis with goiterThyroid stimulating blocking Ab Atrophic thyroiditis

“Spontaneous” mixoedema in the adultTGBI – thyroid growth blocking immunoglobulins

Atrophic thyroiditis“Spontaneous” mixoedema in the adult

Anti T3 –Ab , anti T4 - Ab May interfere with hormone assessment

Anti pancreatic isletAnti salivary ductsAnti neuro-muscle plate

 Diabetes mellitus Sjogren’s syndrome Miastenia gravis

Anti other endocrine glands: pancreas, adrenals, gonads

Poli immune endocrine disease (PIE):Type 1: adrenal failure, diabetes mellitus, mucocutaneous candidiasisType 2 : adrenal failure, autoimmune thyroiditis, autoimmune precocious ovarian failure (or testicular failure)

Relationship between auto anti thyroid antibodies anddiseases produced by these antibodies

The presence of antithyroid antibodies attracts locally lymphocytic infiltration that progressively leads to limitation of functional thyroid tissue and thyroid hypofunction

Formes of autimmune thyroiditis

HASHIMOTO’S thyroiditis: signs and symptoms• goiter• metabolic state• eutiroidism – 80 %• hipothyroidism – 15 %• hiperthyroidism – 5 %• some may have subclinical hypothyrodism with slightly increased TSH and

normal fT4

LABORATORY DATA• T4, T3 are frequently normal• TSH normal or slightly elevated• in autoimmune thyroiditis with thyrotoxicosis TSH is decreased under normal

limits• increased response of TSH to TRH in subclinical or overtly hypothyroid patients• anti TPO – antibodies – 100 %• anti TG-antibodies – 90 %• TSH receptor blocking immunoglobulins – 15-20 %

ULTRASOUND EXAMINATIONTHYROID VOLUME: Increased, normal or decreased Intense hypoechogenicityScintiscan : patchy hypoechogenicity Classical Hashimoto’s thyroiditis has an increased thyroid volume and intense

hypoechogenicity in ultrasound examinationFNB: lymphocytes and Hurthle cellsEvolution: in most cases antithyroid antibodies and lymphocytic infiltration

determine progressive loss in thyroid function with subclinical hypothyroidism and than overt hypothyroidism. Subclinical hypothyroidism means slightly increased TSH, normal T4 and absence of obvious clinical signs and symptoms of hypothyroidism. Subclinical hypothyroidism is a risk factor for hypercholesterolemia, atherosclerosis and ischemic hearth disease

CLINICAL FORMS• HASHOTOXICOSIS: autoimmune thyroiditis and thyrotoxicosis• IN CHILDREN AND ADOLESCENTS: diffuse euthyroid goiter 10-15 % of

goiters at in children and adolescents are produced by autoimmune thyroiditis • ATROPHIC thyroiditis causes “spontaneous” mixedema in adults and elderly

patients• SILENT or PAINLESS thyroiditis occurs mainly between 30-60 years and may

produce hypothyroidism in time• POSTPARTUM THYROIDITIS : TPO-Ab are detectable in predisposed cases in

the 6th month of pregnancy: hyperthyroid state + depression it occurs postpartum weeks 11-12 and is followed by transient or definitive hypothyroidism.

• AUTOIMMUNE THYROIDITIS and MALIGN LYMPHOMA: primary lymphoma of the thyroid may develop in a thyroid previously affected by autoimmune thyroiditis

• AUTOIMMUNE THYROIDITIS and THYROID CANCER. Autoimmune thyroidits is not a factor of predisposition for thyroid cancer. Papillary thyroid cancer in the most frequently associated with autoimmune thyroiditis. A thyroid nodule in a patients with known autoimmune thyroiditis must be assessed as all thyroid nodules in order to confirm a thyroid neoplasia.

• IATROGENIC: interpheron, increased iodine intake, external radiotherapy may also produce autoimmune thyroiditis by interfering with immune system.

TREATMENTTHYROID HORMONES if clinical or subclinical hypothyroidism occurs.Surgery may be done if it a suspicion for an association with thyroid lymphoma

or with a thyroid carcinoma as well in cases in which there are compressive symptoms due to large goiter that does not respond to thyroid hormones treatment or even small goiter that does not respond to hormone treatment

THYROID NODULESThe incidence of thyroid nodules depends of the way of assessment of the thyroid

gland:• CLINICAL : 4-7 % (5-20%)• NECROPSIES:40-50 % (30-60%)• ULTRASOUND EXAMINATION 16-67 %

CLINICA OF ENDOCRINOLOGY IASI: - MEN : 27,37 % - WOMEN: 30,3 % - CHILDREN: 1-2%

• THE PREVALENCE INCREASES WITH AGE BY : 0,08 % / year

THYROID CANCER: < 10 % OF PALPABLE NODULES, <5 % OF NODULES DETECTED BY ULTRASOUDNODULS 4 % OF POPULATION X 4% RISK= POSSIBLE INCIDENCE:

1,6/103

TRUE PREVALENCE : 0.025-0,050/1001/30 THYROID MICROCANCERS BECOME CLINICALY DETECTABLE

Thyroid nodules are more frequent in iodine deficient areas

Lesions that could appear as thyroid nodules• Cyst• Heterogenous endemic multinodular goiter • Adenoma• Thyroiditis• Thyroid cancers• Lymphoma

• Extrathyroidal lesions

AUTHOR (YEAR) INVESTIGATED AREA INCIDENCE OF NODULSReshetnikov 1990 CIS 18,8 %

Filatov 1991 CIS 3,45 %Brander 1991

Finland27,3 %Solitar – 57 %Multinodular 43 %

Hintze 1992 Germany > 60 YEARS Endemic area

24,78 %

Grun 1992 GermanyGoiter prevalence: 37,7 %,

27,6 %women 36 %, men: 18,8 %

Mettler1992 Ukrain, Cernobil area children: 0,5 %Adults 14,9 %

Mogos 1994 Iasi, Romania women: 30,3 %meni: 27,7 %61,84 < 1 cm, 21 % 1-2 cm.9,2 %> 3 cm

Incidence of thyroid nodules detected by ultrasound examination

THYROID CANCERSINCIDENCE Males /106 Females /106

• USA: 2,4-2,8 5,6-6,2• Australia: 0,7 2,1• Japan: 1.1 2• Hawai: 3,1 4• Germany: 2,7• USA: ’85-’95: 13.856 cases = 1 % Cancer Data Base

Necropsies:Honolulu: 15,16%Hiroshima: 25,3USA: 1,09-1,84

There is a trend to increase of papillary thyroid carcinoma in the last decades but its prognosis is very good.

MORBIDITY:NEW CASES /106/ year

• SOKAL 1954: 12 / 106/ year• CUTTLER 1975: women: 52 /106/year

men: 21/ 106/year

• INGBAR 1981: 36 / 106/year• IMPIERI 1984: 10-30 / 106/year• MAZAFFERRY 1988 : 37 / 106/year

In all reported date the incidence of thyroid cancer increases with age and is more frequent in women than in men. The incidence increases with age as well as the severity of the disease concerning tumor stage and histological form. Survival rate decreases with age. The cut-off age being that of 45 years.

Classification of thyroid tumorsBenign – derived from follicular epithelium

• Follicular adenoma• Atipical follicular adenoma• Trabecular adenoma• Oxifilic adenoma• Other adenomas

Benign – non derived from follicular epithelium• Paraganglioma• Teratoma• Mezenchymal tumors

• vascular• myogenic• neural

Thyroid cancersa. Derived from follicular epitheliumDifferentiated • Papillary carcinoma

• Follicular carcinomaUndifferentiated• Anaplastic (undifferentiated carcinoma)

b. Derived from calcitonin producing cells Medullary thyroid carcinoma - MTC- Sporadic MTC- Familial MTC- MTC as part of Multiple Endocrine Neoplasia (MEN) type 2 A and 2B

Other malignan tumors • Derived from lymphocytes

• Hodgkin lymphoma• Nonhodgkin lymphoma• Plasmocitoma

SarcomasMetastasis

Malignant thyroid tumors

Thyroid cancers derived from cell normally located into the thyroid gland, their frequency and prognosis

Causes of thyroid tumors derived from follicular epitheliumDifferentiated thyroid cancer: papillary and follicular carcinoma

- external irradiation is the only established cause for most of papillary thyroid carcinoma. It was first recognized by Duffy and Fitzgerald 1936, after head and neck irradiation for other diseases. Than it was recognized in individual after the nuclear accident from Tcernobil (Ukrain) which was followed by an impressive increase of papillary thyroid carcinoma, especially in children under 14 years (78.8 %).

- iodine intake favor the development and increased incidence of papillary thyroid carcinoma with a very good prognosis, the decrease in incidence of follicular carcinoma with a less good prognosis and decreased impressively the incidence of undifferentiated (anaplastic) carcinoma.

- papillary carcinoma represents till 70 % of thyroid cancers in areas with high or sufficient iodine intake and less in area with iodine deficiency.

- follicular thyroid cancer is more frequent in areas with iodine deficiency as well as undifferentiated thyroid cancer. Taking into account this situation, iodine profilaxis becomes also a profilaxis for the development of aggressive thyroid cancers.

Normal thyroid cell have a proto-oncogene called RET (10q 11.2) that encodes a receptor thyrozine kinase receptor for Glyal-derived Nerve Growth Factor(GDNGF) and Neurturin. Binding of its specific ligand leads to receptor dymerization and a cascade of events involving tyrosine-kinase, Braf and RAS gene

activation that finally result in cell proliferation and cancer development. This gene is not expressed in normal follicular cells but normally expressed in parafollicular cell (calcitonin secreting cells of neural origin).

In papillary thyroid cancer it is supposed that external irradiation produces a breakdown of DNA and during the process of DNA repair RET protoncogene is placed by a translocation mechanism under the control of genes normally express in follicular cells and become activated. This process is called RET/PTC rearrangement and was described first in papillary cancers that occurred after Tcernobil accident and is now discovered in most papillary thyroid carcinomas.

Most of undifferentiated thyroid cancer, with a very poor prognosis are derived from previously diffentiated papillary of follicular cancer due to mutation or lost of Tumors Suppressor Gene – p53.

In medullary thyroid carcinoma point mutations of different codons of RET protooncogene result in different forms of medullary thyroid carcinomas (sporadic or associated with other cancers of cells derived from neural crest (see below).

Clinical presentation of thyroid carcinomas:All forms of thyroid cancers are more frequently in women. Sex ratio depends of the histological form.

Important facts: There are an important differences between differentiated thyroid cancers and other cancers, because differentiated forms preserve the ability to uptake iodine and are sensitive to TSH stimulation. On the bases of these characteristics differentiated thyroid carcinomas may be treated in multimodal way by association between total thyroidectomy and treatment with radioiodine and thyroxine treatment for suppression of TSH and therefore further growth of tumors. For these reasons differentiated thyroid cancer have a good prognosis and a long evolution.

Papillary thyroid cancer. It is the most frequent of thyroid cancers and occurs in 70-80 % on patients residents in areas of sufficient iodine intake. Clinically papillary thyroid carcinoma presents as a solitary thyroid nodule, but multinodular goiter may be also present. Lymph node involvement occurs frequently and some o cases may be announced by previous metastases. In ultrasound examination it presents as a hypoechoic thyroid nodule with irregular margins and microcalcifications.ultrasound guided fine needle biopsy establishes the diagnosis in most cases bringing characteristic cells. The evolution of the disease is slow the tumor remains for a long time confined to the thyroid gland. Most frequent metastases occurs in cervical lymph nodes and than in lung and liver. Bone metastases are rare. Most cases especially those occurring in women under 45 years old have an excellent prognosis.

Follicular thyroid cancer occurs also most frequently in women, later than papillary thyroid cancer. Is more frequently seen in area of iodine insufficiency. Iodine supply in iodine deficient areas decreased the ratio between follicular and papillary thyroid cancer and taking into account that follicular cancer have a less good prognosis than papillary cancers iodine supplementation lead to an overall better prognosis of thyroid

cancers. Clinically follicular carcinoma presents as a solitary thyroid nodule that may invade the adiacent structures and give distant metastases by route of blood to liver, bone and brain and spine. Sometimes the diagnosis is made due to distant metastases. The prognosis is less good than in papillary thyroid cancers. Ultrasound examination reveals a solitary thyroid nodule, with irregular margins, without microcalcifications. Scintigraphy shows a cold nodule. Fine needle biopsy is less relevant because the pathologist may say only that is a “follicular neoplasia” but not certainly a follicular cancer. 40 % of nodules with a biopsy of follicular neoplasm may truly have a follicular cancer. As most differentiated thyroid cancer follicular carcinoma may be treated by total thyroidectomy and radioactive iodine if patient is at high risk: large tumor with surrounding structures invasion, distant metastases, particular histologic forms.

Anaplastic thyroid carcinomaUssualy occurs in old patients, it is more frequently seen in areas with low iodine

supply and the cause is lost of the Tumor Suppressor Gene p53, in some previously differentiated thyroid cancers.

Clinical picture of anaplastic carcinoma is that of a rapidly progressive thyroid tumor, with lymph node involvement, invasion of neck structures with compressive symptoms, and frequently distant metastases at the time of diagnosis.

Medullary thyroid cancer (MTC). It develops from calcitonin-secreting cells which are of neuroectodermal origin.

Calcitonin-secreting cells preserve their ability to produce as other neuroendocrine cells other hormones and mediators: histamine, serotonine, somatostatine, carcino-embrionary antigen, bombesine, ACTH (adreno-corticotropic hormone), CRH (corticotrophin-releasing hormone). The disease is occurs with equal frequency in men and women. More than 70 % of cases occurs as sporadic forms and the others familial forms: isolated familial MTC, MTC as a part of Multiple Endocrine Neoplasia (MEN) type 2A and 2B (see below).

Thyroid tumor may have different dimensions from some millimeters to centimeters, is firm and frequently associated with lymph node involvement. Signs and symptoms of calcitonin and other hormone secretions may produce: flushes (calcitonin ans serotonin), diarrhea (calcitonin), ACTH-dependent Cushing’s syndrome. In familial forms of MEN other signs and symptoms occur: arterial hypertension (pheochromocytoma), hypercalcemia (hyperparathyroidism), ganglioneuromatosis of lips and eyelids (also see below). Increased basal calcitonin and carcinembriogenetic antigen are markers of the disease. In cases in which calcitonin in not obviously elevated calcitonin may be stimulated by pentagastrin or calcium infusion.

Mutations that occurs in codons that are part of RET gene lead to different forms of medullary thyroid carcinoma, sporadic, familial MTC, or Multiple Endocrine Neoplasia

type 2A/B

Syndromes as soc iated with MTC

0 %100 %0 %0 %Marfan-like appearance

0 %100 %0 %0 %Ganglioneuromatozis

0 %0 %< 10 %Codon: 618,620

0 %Notalgia –cutaneous lich en amyloido sisHirschprung disease

0 %0 %10-25 %0 %Hyp erparatiro idism

0 %50%10-60%0 %Pheocromocytoma

rar100%100%100%C cell h yperp lasia

rara100%100%100%Bilateral

rara100%100%100%Multiplicit y

<40<20<20<20,>50Age at diagnosis

100%100%100%100%CMT

10,11,13,1616,(15)10,1110,11,13,14,15Exon

somaticGermlin eGermlin eGerminlineRET mutation

Sporadic MTC

MEN-2BMEN-2AFMTC

Modigliani 2000, Schlumberger M. 2000

MTC and syndromes associated with MTC

A genetic predisposition was also identified in cancers derived from follicular epithelium in carrier for the gene MNG (multinodular goiter)

Evaluation of thyroid nodules and thyroid cancer- thyroid examination- history of the disease in individual and relatives- scintigraphy- fine needle biopsy- TSH, T4, - Antithyroid antibodies- Calcitonin measurementUltrasound examination of thyroid nodules

• Identifies that lesion belongs to the thyroid , if it is solitary or multiple and has or not has lymph node enlargement

• It is the guide for fine needle biopsy

• It allows to detect the anatomic rapports with other structures• Low risk: pure cyst, hyper or isoechoic, transonic hallo, peripheral large

calcification• High risk: irregular margins, microcalcifications, cyst with solid content inside • Color Flow Doppler ultrasound: benign: vascular hallo , a few echos inside the

nodule, malign: intense vascularity inside, transcapsular vesels.

Scintigraphy of thyroid nodulesDifferentiated thyroid cancer CLASSICAL: 131 I most used ( no uptake in the nodule “cold nodule), also used for follow-up

• 99m Tc : false negative in some cases of thyroid cancers. Nodules positive for 99m Tc but without iodine uptake may be cancersNew scinigraphies99 Tc MIBI:

o bone metastasis: sensitivity: 73 %, specificity; 90%o lung metastasis: sensitivity: 21 %, specificity: 94 %

• 99 mTc tetrafosmin• 201 Tl positive for differentiated thyroid cancers

In some cases computed tomography and MRI imaging allows the surgeon to obtain details about the relationship between nodule and surrounding tissues. Computed tomography is not indicated because it may lead to iodine saturation of thyroid tissue and interfere with further radioactive iodine administration after surgery if the nodule was a differentiated thyroid cancer.

Fine needle biopsy in thyroid nodules FNB is the most reliable assessment of thyroid nodules and allows:

• a good detection for papillary, medullary and anaplstic carcinoma• planning for surgery• selection of tumors in which other therapy may be beneficial (lymphoma)• non-conventional therapy for thyroid nodules: cyst evacuation, necrotizating of

functioning adenomas

Assessment of thryoid nodules

Thryroid nodule

ultrasoundcyst Solid or mixed solid and cystic

FNB

MALIGNsuspiciousscintigraph y

coldW ARM

Low risc High risk

THYOIDECTOMYFollow up

FNBBENIGN

T4Ev acuation of

the cyst conyent

persistenceheeling

E.Zbranca si col.Simp .Nat.Endocrinol.1995, Endocrinologie Clinica 1997

Algorithm for diagnosis in thyroid nodules

No reduction or continuous gro wth. Nodules which have high TSH at diagnosis have more chances to b e malignant

Some reduction. Nodules associated with lo w TSH levels at diagnosis are more probable to be b enign

Response to suppresive treatment with thyro id hormones

Suspicious or malign ant“benign”Fine needle b ipsy

“cold nodule”W arm or hot nodule Scinigraph y

Irregular margin s, absen ce of h allo, nodule development more in the depth of the lob e than in its long est, lymp node enlargement, microcalcifications.

Pure cyst, normo echoic or hyp erechoic, periph eral gross calcification

Ultrasound

Increase calcitoninAntith yroid antibodies increasedLaboratory assessment

Solitary nodule, lymph node enlargement, distant metastases

Multiodular goiter, soft nodule without lymp node enlarg ement

Clinical features of the nodule

History of ext ernal irradiation of the neck, family h istory of CMT, so litary nodule with rappid gro wth, compression, male sex, young age, child

Endemci goiter area, h ystoru of benign th yroid patholog y, female sex, advan ced age.

History

Malignancy Benignit yElement

Elements that plead for benignity or malignancy in thyroid nodulesA history of Graves disease of Graves disease in evolution increases the

probability of a nodule to be malign.

Staging of thyroid cancers

ASTEGE IV – orice T, orice N, M1 AND ANAPLAS TI C THY RID CARCI NMA INDEPENDENTLY OF EXTE NSION

STAGE III - T4, N0,M0, orice T,N1,M0

STAGE II - T2 / T3, N0, M0 ATAGE II - anyT, any N, M1

STAGE I - T1, N0, M0STAGE I - any T, any N, M0Patients older than 45 yearsPatients under 45 years

CLINICAL STAGING OF PAPILLARY AND FOLLICULAR CANCERS

STAGING OF MEDULALRY THRY OID CARCINMA

STAGE IV – ANY T, ANY N, M1

STAGE III – ANY T, N1, M0

STAGE II - T2 / T3 / T4 , N0, M0

STAGE I - T1, N0, M0

TREATMENT OF DIFFERENTIATED THYROID CANCERSURGERY

• always total or near total thyroidectomy• loboistmectomy: small papillary carcinoma in low-risk patients, children, young

adultsSide effects :

• laringeal palsy : 2-8 %• hypoparatiroidism: 1-4 %

After surgery patients are classified into:- Low risk: small papillary or follicular carcinoma in women under 45 years old- High risk: larger tumors with lymph node involvement, both sexes after 45 years, toll cell tumors, sclerosing papillary tumors

RADIOACTIVE IODINE IN THE TREATMENT OF DIFFRENTIATED THYROID CARCINOMA

Ablation of thyroid remnant after surgery - In high risk patients is always indicated- controversial in other patients- not indicated in low risk patients- Ablative dose between 30 – 100 mCi depending of the tissue left after surgery and

histology

Treatment and follow-up of patients with differentiated thyroid cancerSuppressive treatment :

• L-Thyroxina >/= 200 mg/day• 2,1-2,8 mg/b.w./day• TSH may be maintained < 0.1 mUI/mlFollow-up:Tiroglobulin (IRMA) is best indicator for cure or persistent or recurrent disease• undetectable in 98 % of those in remission• if detectable when THS values are very high after thyroid hormone withdrawal

there is persistent or recurrent disease and a new dose of radioactive iodine is given

Whole body scanning after T4 withdrawal for 4 week until TSH reaches values of at least 30 mIU/L

rhTSH 0.9 mg may replace thyroid hormone withdrawal in patients who do not tolerate prolonged hypothyroidism

Tg < 10 ng/ml : treatment with radioactive iodine in dose less than 100 mCiTg > 10 ng/ml: treatment with 100 mCiImmediately patients will receive suppressive doses of l-thyroxine

For those with Tg + si WBS negative: 18 F-FDG-PETLung metastases are responsive to large doses of radioiodine and suppressive therapy for TSH with thyroxine. Bone metastases are less responsive and may be surgically removed or irradiated.

TREATMENT AND FOLLOW-UP OF DIFFERENTIATED THYROID CANCERS

Total thyroidectomy131 I ablation and + Whole Body Scanning

3 month (sub fT4:FT3-TSH-Tg

Thyroglobulin> 5 ng/ml

131I100 mCi+WBS

6-12 month- stop T4Determine TSH/Tg131 I WBS (2-5 mCi

Thyroglobulinundetectable

Annualycontrol of Tg on T4

Tg < 10 ng/ml

Tg +131I WBS ( 2-5 mCi)

Negativ: repete every 2-5 years

Tg > 10ng/mlor WBS +

Treatment and fo llow up of medullary thyroid carc inoma

Total thyroidectomy

6 weekCEA,CT,Test

Pentagastrine

N Repeat anulally

Negative Repeat at 2 years

No detectable metastases

Incompeltesurgery

MicrometastasesPG – CT =Nrepeat

Distant metastases

CT<50Pg-CT<500

CT>50PG-CT>500

Repeat anually

Stable disease

Increased calcitoninand CEA

US,CT,RMNnegative

Positron emission scintigraph y)

No tumor detectable

Repeta anu al

Local recuren ce or metastases

Surgery Modigliani 2000

SCREENING AND MANAGEMEN T OF FAMIL IAL MEDULALRY THYROID CARCIN MA AND MEN 2A

Patient with CMT (index case)

Germline mutation for RET

RET positive/hereditary disease

RET mutation anlysis in first degree relatives

Negative

No investigation is necessary

•RET pozitive

RET negative

Pentagastrine test

unsignificant

Minimal riskSurgery as soon as possible

Surgery refused

Test pentagastrin

stimulation test for calcitonin

Pozitive- surgery Negativ repeat annualy PG- CT

In the case of familial MTC or MEN2A/B there are the flowing recommendations for screening of patients with inherited disease (vide supra).

Anaplastic thyroid cancer could be treated by surgery, followed by external irradiation and chemotherapy, but survival is very poor independently of the treatment .