thyroiditis inflammatory diseases of the thyroid gland with different etiologic, biologic,...

THYROIDITIS

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 THYROIDITIS

Signs and symptoms• Fever

• Pain profound and severe

• Dysfagia - 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

ACUTE BACTERIAL THYROIDITIS

Acute thyroiditis - histology

SUBACUTE ”DE QUERVAIN’S” THYROIDITIS

PREVALENTA

Sex ratio F/M: 3,6/1 – 10,6 /1

1 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

Szabolosz I. Subacute thyroidits Budapesta 2000

SUBACUTE THYROIDITIS

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 clincal symtoms

• it has no relatioship with the evolution of the disease


PATOGENICITY• interleukine 6 produced by monocytes si macrophages determine inflammation

• interleukine 2 +TNF + interferon 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 67 Gallium citrat: scintiscan


Differential diagnosis Evolution and complications

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

Painless forms

Transient hypothyroidism second phase of evolution Recurrent disease is unpredictable Heeling Definitive hypothyroidism <1/10

Subacute thyroiditis: generalized hypoechogenicity

Subacute thyroiditis: patchy hypoechogenicity


Color Doppler ultrasound examination scintiscan

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

FORME USOARE:

Nonsteroidal anti inflammatory drugs: indometacin

AUTOIMMUNE THYROIDITIS

INCIDENCE

• 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 U.I./ml

• 60 % of those with TSH > 6 U.I./ml have antithyroid antibodies

• 80 % of those with TSH > 10 6 U.I./ml have antithyroid antibodies

• 5 % of those with TSH > 6 U.I./ml develop overt hypothyroidism each year


PATOGENY

• genetic predisposition

•Viral aggression

• excessive iodine supply

GENETIC PREDISPOSITION

• relatives with autoimmune thyroid diseases

• patients with genetic abnormalities :Turner, Klinefelter, Down syndrome

• association with other autoimmune diseases:

• multiple autoimune endocrine diseases type I and II (ICSR, ovarian failure with precocious menopause ) autoimmune hypophysitis Biermer disease , sd, Sjogren, lupus, rheumatoid arthritis , miastenia gravis, interstitial lung disease

• HLA-DR3 si HLA-DR4


ANTIBODIES THIROIDITIS

ANTI-TPO (PEROXIDASE) HH, PTP

ANTI – Tg Ab HH

TSH -receptor stimulating antibodies hashitoxicosis

TGI – thyroid growth immunoglobulins HT with goiter

Thyroid stimulating blocking Ab Atrophic thyroiditis

Spontaneous mixoedema

TGBI – thyroid growth blocking immunoglobulins

Atrophic thyroiditis

Spontaneous mixoedema

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

Anti pancreatic islet

Anti salivary ducts

Anti other nedocrine glands Multiple autoimmune endocrine diseases


HASHIMOTO’S thyroiditis

• goiter

• metabolic state

• eutiroidism – 80 %

• hipothyroidism – 15 %

• hiperthyroidism – 5 %

LABORATORY DATA

• T4, T3 frequently normal

• TSH normal or slightly elevated

• increased response of TSH to TRH

• anti TPO – ab – 100 %

• anti TG-ab – 90 %

• TBII – 15-20 %

ULTRASOUND EXAMINATION

THYROID VOLUME: Increased, normal or decreased

Intense hypoechogenicity

Scintiscan : patchy hypoechogenicity FNB: lymphocytes and Hurthle cells

TREATMENT

THYROID HORMONES


CLINICAL FORMS• HASHOTOXICOSIS

• IN CHILDREN AND ADOLESCENTS: diffuse euthyroid goiter 10-15 % of goiters at these ages

• ATROPHIC

• SILENT or PAINLESS

• POSTPARTUM THYROIDITIS : TPO-Ab are detectable in predisposed cases in the 6th month of pregnancy: hiperthyroid state + depression it occurs postpartum weeks 11-12 and is followed by transient or definitive hypothyroidism

• AUTOIMMUNE THYROIDITIS SI MALIGN LYMPHOMA

• AUTOIMMUNE THYROIDITIS and THYROID CANCER

• IATROGENIC: interpheron, increased iodine intake, external radiotherapy

AUTOIMMUNE THYROIDITIS-HISTOLOGY

AUTOIMMUNE THYROIDITIS CLINICAL ASPECT

POSTPARTUM - AUTOIMMUNE THYROIDITIS

AUTOIMMUNE THYROIDITIS - ULTRASOUND


ATROPHIC VARIANT

THYROID NODULES

THYROID NODULES• 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 US

NODULS 4 % OF POPULATION X 4% RISK= POSSIBLE INCIDENCE: 1,6/103

TRUE PREVALENCE : 0.025-0,050/103

1/30 MICROCANCERS BECOME CLINICALY DETECTABLE (MEYER 2000)

THYROID NODULES

•CYST

• HETEROGENOUS ENDEMIC GOITER

• ADENOMA

• THYROIDIS

• CANCER

• LYMPHOMA

• EXTRATHYROIDAL LESION

THYROID NODULESAUTHOR (YEAR) INVESTIGATED AREA INCIDENCE OF NODULS

Reshetnikov 1990 CIS 18,8 %

Filatov 1991 CIS 3,45 %Brander 1991

Finlanda27,3 %Solitar – 57 %

Multinodular 43 %

Hintze 1992 Germany > 60 YEARS

ENDEMIC AREA24,78 %

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

THYROID CANCERS

INCIDENCE B/106 F/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 25,3

USA: 1,09-1,84

MORBIDITY:NEW CASES /106/ year

• SOKAL 1954: 12 / 106/ year

• CUTTLER 1975: femei: 52 /106/year

barbati: 21/ 106/year

• INGBAR 1981: 36 / 106/year

• IMPIERI 1984: 10-30 / 106/year

• MAZAFFERRY 1988 : 37 / 106/year

THYROID CANCERS

THYROID CANCER papillary form

FOLLICULAR THYROID CANCER

MEDULLARYTHYROID CANCER

THYROID LYMPHOMA

Steady increase of thyroid cancer all over the world

Between 1973-2002Between 1973-2002

2.4 times increase in 2.4 times increase in thyroid cancer incidencethyroid cancer incidence

All thyroid cancerAll thyroid cancer 3.6/103.6/1055

8.7/108.7/1055/year/year

Papillary cancerPapillary cancer 2.7/102.7/1055

7.7/107.7/1055/year /year

Small papillary Small papillary cancer cancer

87 % of the cancer 87 % of the cancer increaseincrease

Mortality decreased from Mortality decreased from 0.57 to 0.47/100.57 to 0.47/1055/year/year

external irradiation stopped external irradiation stopped after 1961after 1961

precocious diagnosis by precocious diagnosis by ultrasound and FNB ultrasound and FNB

increased incidence but increased incidence but stable mortalitystable mortality

Papillary cancer has a long Papillary cancer has a long evolution and excellent evolution and excellent survivalsurvival

Trends in thyroid cancer

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

External irradiation is 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

The ratio of papillary to follicular thyroid cancer

(M.Goldust, S.Samankan etc al,2012)

(J. D. Cramer, 2010)

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

Table 1. Demographic data of 345 patients with thyroid cancer operated between 1975-2009 in the Ist. Surgery Clinic

of 5 years from the entire examined cohort

Figure 4. Percentage of thyroid cancer operated for each period

Etiology and patogeny of thyroid cancers

external irradiation:“ ..until now the only carcinogenetic factor for the thyroid in man is external irradiation

Duffy si Fitzgerald 1936: firs obsercation of radiatioon induced thyroid cancer in children irradiated for benign lesions of head and neck

New cases of thyroid cancer in in Belarus 1990-1995 –Cernobil effect

( Pacini: J.Clin.Endorinol.Metab.1997)

1990 – 31, 1991 – 66, 1992 – 72, 1993 – 94, 1994 – 96, 1995 – 90 78.8 % sub 14 ani

Prezumed thyroid cancer: 10- 40 Excess of thryodi cancer due to external irradiation after Cernobil: 200 - 800

Increased susceptibility:

Irradiation of head and neck in all children

- external irradiation for othe rcancers

-Vage less than 20 years

-Female sex

-Genetic predisposition

CONTAMINAREA RADIOACTIVA DUPA CERNOBIL 1986

THYROID CANCER – CERNOBIL ACCIDENT

Irradiation induced thyroid cancer

(E.Cardis,2005).

(E.Cardis,2005).

(E.Cardis,2005).

THYROID CANCER

THYROID CANCERFCMT MEN-2A MEN-2B CMT

sporadic

RET MUTATION germinal germinal germinal somatic

Exon 10,11,13,14,15 10,11 16,(15), 918 10,11,13,16

CMT 100% 100% 100% 100%

AGE <20,>50 <20 <20 <40

Multicentricity 100% 100% 100% rara

Bilateral lesions 100% 100% 100% rara

Hiperplasia of C cells 100% 100% 100% rar

Feocromocytoma 0 % 10-60% 50% 0 %

Hiperparathiroidism 0 % 10-25 % 0 % 0 %

Notalgia –cutaneous lichen amyloidosis

Hirschprung disease

0 % < 10 %

Codon: 618,620

0 % 0 %

Ganglioneuromatosis 0 % 0 % 100 % 0 %

Dismorphism 0 % 0 % 100 % 0 %

MEN TYPE IIB - GORLIN’S SYNDROME

THYROID CANCER- ultrasound exam

THYROID CANCER

THYROID CANCER - FNB

Risk factors for malignancy in thryoid nodules

element benign malignant

history Endemic area, female sex, aged patients

History of cranial irradiation, other medullary thyroid carcinomas in the family, solitary thyroid nodule rapidly growing, compressive symptoms, male sex, child, young adult

Clinical data Multinodular goiter,soft nodule, lack of palpable lymph nodes,

Solitary ferm nodule, lymph node enlargement, distant metastases

Biologgical data AAT+, deceased TSH ,increased T3,T4 Increased calcitonine

ultrasoud Pure cyst, peripheral hallo, hyper, iso or hypoechoic, without calcification. Doppler exam:peripheral ring of vassels

Irregular margins, absence of hallo, increased intranodular vascularity

scintigraphy “worm nodule” a cold nodule is not surely a malignant one

“cold nodule”

ABC (FNB) “benign” Suspicious or malignant

Response to thyroid hormone treatment

Reduction of volume Increased volume under treatment

FINE NEEDLE BIOPSY

Algorithm for investigation and treatment of thyroid nodules

TYOROID NODULE

ULTRASOUNDCYST SOLID or partially cyst

FNB

MALIGNSUSPECT SAU NEOPL.FOLIC

SCINTIGRAPHY

COLDWARM

LOW RISK HIGH RISK

THYROIDECTOMY

Follow up

FNB

BENIGN

T4

ASPIRATION

SCLEROSING

REFACEREHeeled

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

Clinical staging of differentiated thyroid cancer

Patients under 45 years old Patients over 45 years old

STAGE I - any T, any N, M0 STAGE I - T1, N0, M0

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

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

STAGE IV – any T, any N, M1

Papillary and follicular

Clinical staging of medullary thyroid carcinoma

STAGE I - T1, N0, M0

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

STAGE III – any T, N1, M0

STAGE IV – any T, any N, M1

Treatment of diffentiated thyroid cancers

Surgery

• total thyroidectomy +control of lymph nodes

• loboistmectomy: only in microcarcinomas with low risk (young age, female sex, well differentiated papillary

Complication:

• recurrent nerve palsy: 2-8 %

• hipoparathyroidism: 1-4 %

• intra or postoperative hemorrhage

Treatment of diffentiated thyroid cancers

Radioactive iodine - 131I

Indication (Schlumberger 2000)- incomplete surgery

- compete surgery with risk of reccurence: less than 16 years or > 45 ani

- papillary variant less differentiated: columnar, diffuse sclerozing

- faollicular variant: invasive, less differentiated, Hurthle cell

- large tumors with capsular invasion

- Tiroglobulin over 3 ng/ml after 3 month of treatment

Ablative iodine therapy: 30 mCi or more if a certain volume of cancer tissue was left in place

Iodine therapy after previous ablation: 100-150 mCi for local recurrences or distant metastases

for children: 1 mCi/Kg bw

Treatment and follow up of differentiated thyroid cancers

Suppressive thyroxine treatment :

• L-Thyroxine >/= 200 g/day

• 2,1-2,8 g/Kg.bw/day

• for TSH < 0.1 UI/ml

Suppression is switched to replacement dosage if there are not risk factors, serum Tg levels are less than 1 ng/mL

Follow Up:

Tiroglobuline (IRMA) after total thyrodectomy

• not detectable in 98 % of those with remission

• detectable in 5 % of those with reccurences

• in those with reccurences or metastases increaeses after T4 withdrawal (56 %) of after rhTSH (52%)

• errors: AAT tg.

• RT-PCR mARN for Tg

WBS: every 6-12 luni:Tg < 10 ng/ml : 100 mCi2-5 mCi

Tg . 10 ng/ml: 100 mCi

For Tg + si WBS negativ: 18 F-FDG-PET

Protocol for hr TSH adminstration prior diagnostic or therapeutic 131 Iodine administration0.9 mg hrTSH day 1 and 2131 Iodine id given day 3TG measurements in days 1-3-5WBS in day 5

Treatment of diffentiated thyroid cancer

Total thyroidectomy131 I ablation + WBS

3 month fT4:FT3-TSH-Tg Tg> 5 ng/ml

131I100 mCi+WBS

6-12 luni- stop T4TSH/Tg

131 I WBS (2-5 mCi

Not detectable

Yearly Tg control on T4

Tg < 10 ng/ml

Tg +131I WBS ( 2-5 mCi)

Negative: repeat every 2-5 years

Tg > 10ng/ml or WBS +

DIFFERENTIATED THYROID CANCER TREATMENT

1. THYROIDECTOMY AND LYMPH NODE DISSECTION

2. RADIOIODINE TREATMENT

3. HIGH DOSES OF THYROID HORMONE – LT4 TO SUPPRESS TSH

4. INTERRUPTION OF THYROID HORMONE FOR 4 WEEKS TO ALLOW TSH TO INCREASE AND TO STIMULATE IODINE UPTAKE IN NEOPLASTIC CELLS

5. THYROGLOBULIN ASSESSMENT: IF > 10 ng/dL

6. THYROID AND WHOLE BODY SCANNING + RADIOIODINE TREATMENT IF METASTASES OR LOCAL RECURENCE ARE DETECTED

7. THYROID HORMONE AT SUPPRESSIVE DOSES

Treatment and follow up of medullary thyroid cancers

Total thyroidecotmy

Every 6 month

CEA,CT,Test PG

N Repeat yearly

N Repeat at 2

years

No meta

Incomplete surgery

Micrometa

PG – CT =N

Repat anually

Distant meta

Medical treat.

CT<50

Pg-CT<500

CT>50

PG-CT>500

Repat yearly

Stable.follow

increasedUS,CT,RMIN

negatives

Immunoscintigraphy

No tumor

Repeat annually

Lymph nodes meta

Modigliani 2000

MEN 2A or 2B

Patient with MTC (index case)

Germ line mutation of RET analysis

RET pozitive/hereditary disease

RET mutation analysis in first degree relatives

Negative

No other investigation needed

•RET positive

RET negative

PG-CT test

No calcitonine increaseSurgery as

soon as possible if some aggressive mutation are detected

Surgery postponed

Test PG-CT

Positive- surgery Negative repeat PG- CT every year

THYROID CANCER- SURVIVAL RATE

0

20

40

60

80

100

120

0 5ANI 10 ANI 15 ANI

PAPILAR

FOLICULAR

MEDULAR

NEDIF

thyroiditis inflammatory diseases of the thyroid gland with different etiologic, biologic,...

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