DIFFERENTIATED THYROID NEOPLASIA: CLASSIFICARION AND INITIAL INVESTIGATION Alfredo Pontecorvi &...
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Transcript of DIFFERENTIATED THYROID NEOPLASIA: CLASSIFICARION AND INITIAL INVESTIGATION Alfredo Pontecorvi &...
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DIFFERENTIATED THYROID NEOPLASIA:CLASSIFICARION AND INITIAL
INVESTIGATION
Alfredo Pontecorvi & Pietro LocantoreCattedra di Endocrinologia
Policlinico GemelliUniversità Cattolica del Sacro Cuore
FOCUS ON ENDOCRINE NEOPLASIA - Roma 09-10 Luglio 2010
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Motivi più frequenti di riscontro occasionale di nodulo tiroideo
• ECD vasi epiaortici
• Screening ecografico dal ginecologo
• Familiarietà tireopatica
• Aritmie cardiache
• Visita dietologica
• Mal di gola, disfagia, ecc.
• Screening “in piazza”
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The widespread use of ultrasonography has resulted in a dramatic increase in the
prevalence of clinically inapparent thyroid nodules
- Mortensen et al., JCEM 1955 - Gharib, Mayo Clin Proc 1994- Ezzat et al., Arch Intern Med 1994
The epidemic of thyroid nodules
-Tan & Gharib, Ann Intern Med 1997 -Ross, UpToDate, 2005
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Thyroid nodule:a common clinical problem
• In iodine-sufficient areas the prevalence of palpable thyroid nodules ranges between 3-7% of the population
• In mild to moderate iodine-deficient areas (i.e.: Italy) the prevalence is higher (~10%)
• Thyroid nodules are more common: in elderly persons in women in subjects with a history of radiation exposure
1) Tunbridge et al., Clin Endocrinol 1977 2) Vander et al., Ann Intern Med 1968
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at autopsy or by USby palpation
Pre
vale
nce
( %)
Mazzaferri 1993
70
0
10
20
30
40
50
60
0 10 20 30 40 50 60 70 80 90
Age (years)
Prevalence:
The epidemic of thyroid nodules
by palpation
at autopsy or US
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Ultrasound prevalence of thyroid nodules
Author Country Frequenecy Prevalence (MHz) (%)
Carroll USA 10.0 67Horlocker USA 10.0 46Stark USA 10.0 40Brander Finlandia 7.5 27Tomimori Brasile 7.5 17Woestyn Belgio 5.5 19
Range: 19-67%
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• Primary need is to exclude the presence of a thyroid malignant lesion, independent of nodule size
• Because of the high prevalence of nodular thyroid disease, it is neither economically feasible nor necessary to: submit all thyroid nodules to surgery submit all thyroid nodules for a complete assessment of their structure and function
• It is essential to develop and follow a reliable, cost-effective strategy for diagnosis and treatment of thyroid nodules
Preoperative Diagnosis of Thyroid Nodules
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• Vast majority of nodules are asymptomatic
• Absence of symptoms does not rule out malignancy
• Risk of cancer similar in a solitary nodule and MNG
History and Physical Examinationin Patients with a Thyroid Nodule
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Prevalence of Occult Thyroid Carcinoma
Method Author Subjects
(n)
Prevalence
(%)Autopsy Mortensen,1955
Silversbeg, 1966
Fukunaga, 1971
Sampson, 1974
1000
300
100
157
2,8
2,7
24
5,7
Surgery Delides, 1987
Pelizzo, 1990
611
277
1,8
10,5
Burguera and Gharib 2000
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Prevalence of thyroid nodules at US = 30-50/100 pts.
Thyroid US = Autoptic exam
Prevalence of “Autoptic” Ca = ~ 5/100
Estimated Prevalence of “Clinical” Ca = ~5/1000
Thyroid US detects 9 out of 10 cancers that would probably remain silent throughout life
Thyroid Nodule vs. Thyroid Carcinoma
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• Yearly incidence of thyroid cancer is increasing (rank #8)
• In the USA ≈ 23,500 cases of differentiated thyroid cancer are diagnosed each year
Gharib, Mayo Clin Proc 1994Belfiore et al, Acta Endocrinol 1989 Hodgson et al., Ann Surg Oncol 2004 Jemal et al., Cancer J Clin 2005
Thyroid Nodules and Thyroid Cancer
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Trends in Incidence and Mortality of Thyroid Cancer (1973-2002) and
Papillary Tumors by Size (1988-2002) in the United States
Davies L et al., JAMA 2007
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High incidence of thyroid cancer
13.2/105 inhabitants/year(total: ~ 670 cases/year in Sicily)
Papillary Thyroid Cancer (PTC) represents ~ 90% of all thyroid cancers
11.6/105 inhabitants/year
Thyroid Nodules and Thyroid CancerThyroid Tumor Registry of Sicily (2002-2004)
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89,7%
1,1%1,2%8%
Papillifero
Anaplastico
Follicolare
Midollare
Carcinoma TiroideoIstotipo
Registro Tumori Tiroide - Regione Sicilia (2002-2004)
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• Benign tumors
- Follicular adenomaFollicular adenoma
Colloid
Embryonal
Fetal
Hurtle cell
- Papillary adenoma
- Teratoma
• Malignant tumors- Papillary carcinoma
Pure papillary
Mixed papillary/follicular
(tall cell, follicular, oxyphil, solid)
- Follicular carcinoma
Hurtle cells
Clear cells
Insular carcinoma
- Medullary carcinoma
- Undifferentiated
- Miscellaneous
Lymphoma, Sarcoma, Squamous cell carcinoma, Metastatic tumors
Neoplasms of the thyroid
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ATA Guidelines for management of thyroid nodules
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Nodulo Tiroideo Diagnostica Morfo-funzionale
• Data clinici e anamnestici
• Funzionalità tiroidea
• Scintigrafia
• Ecotomografia
• Agoaspirazione (FNA)
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• Race • Age <20 or >70 years• Male sex• Persistent hoarseness, dysphonia or dysphagia• Firm or hard consistency, fixed nodule• Growing nodule• Cervical adenopathy• Thyroid function
Physical Datain Patients with a Thyroid Nodule
Factors suggesting increased risk of malignant potential:
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• History of thyroid cancer in one or more first degree relatives
• History of cancer syndromes with TC (i.e: FAP, Cowden, etc.)
• History of external beam radiation as a child
• Exposure to ionizing radiation in childhood or adolescence
• Environmental factors
• Prior hemithyroidectomy with discovery of thyroid cancer
• MEN2/FMTC-associated RET protooncogene mutation
• 18FDG avidity on PET scanning
• Calcitonin >100 pg/mL
High-risk history
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Nodulo e Cancro della Tiroide: fattori ambientali
Hawaii: l’incidenza è la più elevata del mondo
(soprattutto uomini cinesi e donne filippine)
Sicilia: Elevata incidenza carcinoma papillifero
Ruolo metalli pesanti, radiazioni, carenza iodica ?
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Prevalenza di carcinoma papillifero della tiroidein soggetti esposti a fall-out radioattivo (Chernobyl)
0
20
40
60
80
100
120
140
160
1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997
BambiniAdolescentiGiovani adulti
Num
ero
di c
asi
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Nodulo Tiroideo Diagnostica Morfo-funzionale
• Data clinici e anamnestici
• Funzionalità tiroidea
• Scintigrafia
• Ecotomografia
• Agoaspirazione (FNA)
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Nodulo tiroideoFunzionalità tiroidea
Il riscontro di valori di TSH ridotti
o ai limiti inferiori della norma,
specie se in presenza di gozzo multinodulare,
suggerisce l’esecuzione della Tireoscintigrafia
per valutare la presenza di noduli tiroidei
autonomamente funzionanti
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Scintigrafia tiroidea
Nodulo tiroideo (> 1 cm)
Nodulo freddonon irradiato <10% malignoirradiato 30-40% maligno
Nodulo caldo o isocaptante TSG-I123 < 1% maligno TSG-Tc99 < 5% maligno
~ 10% ~ 90%
* Discordanza tra 99Tc vs. 131I = 3-5%
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Nodulo Tiroideo Diagnostica Morfo-funzionale
• Data clinici e anamnestici
• Funzionalità tiroidea
• Scintigrafia
• Ecotomografia
• Agoaspirazione (FNA)
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Nodulo tiroideoLa rivoluzione ecotomografica
• Più sensibile della palpazione
- noduli < 1,0 cm
- noduli localizzati posteriormente
• Più sensibile della tireoscintigrafia
• Troppo sensibile?
- incidentaloma tiroideo
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Nodulo tiroideoVantaggi dell’ecotomografia
1. Misura diametri e volume del nodulo (tempo 0’)
2. Identifica altri noduli non palpabili
3. Individua alcune caratteristiche di sospetto
4. E’ di ausilio all’FNA
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Identificazione ecografica di ulteriori noduli tiroidei
in pazienti con apparente singolo nodulo tiroideo
Autore Paese Frequenza sonda (MHz)
Pazienti
(n)
Paziente con >1 nodulo (%)
Scheible et al. USA 10.0 73 40
Walker et al. Europa 7.5 200 20
Brander et al. Finlandia 7.5 32 48
Tan et al. USA 7.0 151 48
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Nodulo Tiroideo Caratteristiche ecografiche di sospetto
• Ipoecogenicità
• Assenza della capsula e margini irregolari
• Microcalcificazioni
• DAP > DT (“taller than wider”)
• Vascolarizzazione intranodulare disordinata
• Linfonodi laterocervicali sospetti
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Nodulo tiroideo: struttura
63-78% dei carcinomi tiroideisono ecograficamente ipoecogeni
Isoecogeno Ipoecogeno
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- margini irregolari e poco definiti- alone ipoecogeno assente
- margini regolari e definiti- alone ipoecogeno presente
Nodulo tiroideo: margini
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Nodulo tiroideoInfiltrazione tessuti circostanti
Margini irregolari e infiltrazione muscolare
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“Taller than wider”
Nodulo tiroideo: forma
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Nodulo tiroideo con microcalcificazioni interne
- particelle iperecogene non ecoattenuanti
- elevata specificità (76-93%) - elevato PPV (76%) - bassa sensibilità (36-59%) - prevalenza nei Ca papilliferi (corpi psammomatosi) Microcalcificazioni
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Nodulo tiroideo con macrocalcificazioni
Calcificazioni anche nei noduli benigni:- capsulari, sottili, “a guscio
d’uovo”
- intranodulari e grossolane
“ a zolle”
Macrocalcificazioni
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Nodulo tiroideo ECD: disorganizzazione vascolare
Carcinoma midollare bilaterale
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US features suggestive for malignancy
Sipos. Thyroid, 2009
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US features suggestive for malignancy
Rago T et al, EJE 1998
Quadro ecografico predittivo di malignità soprattutto quando coesistono
più caratteri di sospetto
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Metastasi linfonodale di carcinoma tiroideo papillifero
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Nodulo tiroideo Identificazione linfoadenopatie secondarie
• Forma rotonda (DL/DAP<1.5)
• Ilo vascolare assente o eccentrico
• Microcalcificazioni
• Lacune fluide (necrosi)
• Corticale ispessita e ipoecogena
• Vascolarizzazione corticale con sovvertimento
della angioarchitettura
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Elastography: New Developments in Ultrasound for Predicting Malignancy in Thyroid Nodules
Rago T et al, J Clin Endocrinol Metab 2007
Ela
sti
cit
à
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• US is a very subjective method and highly dependent on the skill of the performer
• Four expert radiologists independently reviewed US images twice at 6-week intervals
• Echogenicity, composition, margin, shape, calcification, vascularity were evaluated.
• Overall sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for the four radiologists were 88.2%, 78.7%, 76.2%, 89.6%, and 82.8%, respectively
• Experienced radiologists showed more than a moderate degree of agreement in US assessment of thyroid nodules, and their final assessments were highly accurate.
Ultrasonography Variability
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Nodulo Tiroideo Diagnostica Morfo-funzionale
• Dati clinici e anamnestici
• Scintigrafia
• Funzionalità tiroidea
• Ecotomografia
• Agoaspirazione (FNA)
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Agoaspirazione Tiroidea (FNA)
• Effettuabile ambulatoriamente
• Senza anestesia
• Ago sottile (23-27G)
• 2-3 aspirazioni/nodulo
• Elevata sensibilità e specificità FN = 2-4%, FP = <1%
5-20% prelievi indeterminati
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The American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer, November 2009
Nodulo tiroideo: quali noduli tiroidei sottoporre a FNA?
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Classificazione clinico-citologica su agoaspirato delle lesioni nodulari tiroidee
(Consensus Italiana SIAPEC/IAP – Ott 2007)CLASSE DIAGNOSTICA
CATEGORIA DIAGNOSTICA
TRATTAMENTO RACCOMANDATO CORRISPONDENZA ISTOLOGICA
TIR-1 Non diagnostico/ non rappresentivo
Non diagnostico: ripetizione dopo 1 meseCisti/emorragia: controllo e/o ripetizione
Cisti
TIR-2 Negativo per cellule maligne Controllo clinico. A giudizio del clinico o su suggerimento del citopatologo si puo ripetere per minimizzare i FN
Gozzo nodulare; nodulo adenomatoso microfollicolare in gozzo; tiroidite
TIR-3 Inconclusivo/indeterminato (proliferazione follicolare)
Asportazione chirurgica della lesione ed esame istologico. Non esame estemporaneo. Decisione presa sulla base del contesto clinico-strumentale. Alcuni marcatori possono essere utili nella discriminazione tra casi chirurgici e casi medici (GAL-3, HBME-1, CK19)
Adenoma follicolare; neoplasie a cellule ossifile; carcinoma follicolare minim. invasivo; carcinoma papillare var. follicolare
TIR-4 Sospetto di malignità Eventuale ripetizione della FNC a giudizio del clinico o su suggerimento del citopatologo. Asportazione chirurgica della lesione con eventuale esame estemporaneo
Prevalentemente varietà follicolare del carcinoma papillare
TIR-5 Positivo per cellule maligne Intervento chirurgico per i carcinomi differenziati (anche in considerazione del contesto clinico). Prosecuzione dell’iter diagnostico in caso di ca. anaplastico, metastasi o linfoma
Neoplasia maligna
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Necessità per il citologo di ottenere una
scheda clinica che riassuma i principali
dati anamnestici e clinico-strumentali
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• Tireoglobulina
• Calcitonina, CEA, Cromogranina A, PTH
• HBME-1
• Galectina-3
• Citocheratina 19
• ret/PTC
• Rb
• p53
• p21, p27
• PPAR (?)
• BRAF
Carcinomi Tiroidei Markers Immunocitochimici (ICC)
Markersdi identificazione
Markersdi malignità o
prognostici
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HBME-1 and Galectin-3
• In combination with Galectin-3, HBME-1 represents
a very useful diagnostic marker
• This combination helps in better identifying malignant
neoplasms of the thyroid (especially papillary
carcinoma) even on fine-needle aspiration biopsies.
De Matos et al, Histopathology 2005 Papotti et al, Mod. Pathol. 2005 Rossi et al, Cancer 2005Rossi et al, Histopathology 2006
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NODULO FOLLICOLARE
(TIR 3)
Polimorfismo
Nucleare ICC Polim. Nucl.
+ ICC
SENSIBILITA’ 96% 100% 100%
SPECIFICITA’ 70,8% 76,4% 92,3%
ACCURATEZZA DIAGNOSTICA
83,7% 89,1% 97%
VALORE PREDITTIVO POSITIVO
77,4% 83,3% 95%
VALORE PREDITTIVO NEGATIVO
94,4% 100% 100%
Nodulo Follicolare Morfologia e ImmunoCitochimica
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• TSH-R
• Gs-• H-, K- e N-ras
• Ret/PTC
• BRAF
• Trk
• PAX8-PPAR• MdmX
• p53
Molecular genetics of thyroid diseaseGeni implicati nella trasformazione neoplastica tiroidea
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• V900E accounts for almost all BRAF oncogenic mutations
• V900E down-regulates major tumor suppressor genes and thyroid iodide-metabolizing genes and up-regulates of cancer-promoting molecules
• Worse prognosis (clinical progression, recurrence, and treatment failure)
• BRAF mutation will likely have significant impact on the clinical management of PTC.
Role of BRAF mutation in PTC
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Sun et al, JCEM 2010
BRAF mutation in cytological diagnosis of PTC
1074 pazienti
Sensibilità FNA aumentata da 67,5 → 89,6%
Accuratezza diagnostica aumentata da 90,9 → 96,6%
9 casi di PTC identificati solo da analisi BRAF
5 falsi positivi di BRAF
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Algorithm for the evaluation of patients with one or more thyroid nodules
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DIFFERENTIATED THYROID NEOPLASIA:CLASSIFICARION AND INITIAL
INVESTIGATION
Alfredo Pontecorvi & Pietro LocantoreCattedra di Endocrinologia
Policlinico GemelliUniversità Cattolica del Sacro Cuore
FOCUS ON ENDOCRINE NEOPLASIA - Roma 09-10 Luglio 2010
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Trends in Incidence and Mortality of Thyroid Cancer (1973-2002) and
Papillary Tumors by Size (1988-2002) in the United States
Davies L et al., JAMA 2007
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Strength of Panelists’ Recommendations Based on Available Evidence
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US features suggestive for malignancyColor flow doppler sonography
Rago T et al, EJE 1998