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Dobrinja, Chiara (2014) Papillary thyroid cancer gender disparity. [Tesi di dottorato]

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Abstract (inglese)

Cancer gender disparity in incidence, clinical presentation, disease aggressiveness, and prognosis has been observed for a variety of cancers.
The more aggressive types of thyroid cancer, anaplastic thyroid cancer and medullary thyroid cancer have similar incidence in men and women. Meanwhile, differentiated thyroid cancer of follicular cell origin, such as follicular thyroid cancer and papillary thyroid cancer are more common in women.
Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer, accounting for approximately 80% of cases. Its incidence has nearly doubled over the last 30 years and is thought to be due in part to earlier diagnosis of subclinical disease.
The rate of PTC among woman is nearly three times higher than men but in most studies males gender is associated with a lower disease free survival and higher mortality [1-6].
Our intention was to consider our experience about the gender disparity in patients underwent surgery for PTC comparing females (F) vs males (M) as regards a series of clinical, histopathologic, molecular, and hormonal variables to determine if, as in breast carcinoma , there is actually a role of estrogens in the pathogenesis of PTC.
Then, in a little series of patients we evaluated the presence of estrogen receptors on the surgical specimen to identify the eventual medical targeted therapy for this type of tumor.
We considered 658 patients underwent surgery for PTC from 2007 to 2011 at the Institute of 2nd Clinical Surgery , University of Padova, and General Surgery Department, University of Trieste. We revised clinical and histopathologic documents and we compared F vs M as regards the following variables: age, extension of surgery, node dissection, TNM, mono/plurifocality, BRAF mutations, and outcome. A p value less than 0.05 was considered statistically significant.
In 10 selected patients, we analyzed the expression of ER- alpha receptors and ER –beta by immunohistochemical studies in the sections of formalin-fixed tissue , paraffin-embedded tumor of the thyroid. We have divided patients in two categories: < 40 years old and > 40 and then we compared the two groups.
Comparing F vs M we observed: the F was 489 (74%) vs 169 M (26%) (p<0.015), the mean age was 46 years (range 11-86) in F vs 46 years (range 11-83) in M (p=<0.44), total thyroidectomy was realized in 474 F (97%) vs 161 M (95%) (p<0.72), loboistmectomy was realized in 13 females (3%) and 8 males (5%) (p<0.83), node dissection was realized in 387 (79%) F vs 132 (78%) M (p<0.99), central node dissection in 340 (88%) F vs 94 (71%) M (p<0.75), laterocervical node dissection in 47 (12%) F vs 38 (29%) M (p<0.011), stage I was in 315 (64%) F vs 87 (51.5%) M (p<0.19), stage II in 15 (3%) F vs 4 (2.5%) M (p<0.51), stage III in 126 (26%) F vs 54 (32%)M (p<0.249), stage IV in 33 (7%) F vs 24 (14%) M (p<0.223), monofocality was in 279 (57%)F vs 89 (52.7%) M (p<0.64), plurifocality was in 210 (43%) F vs 80 (47.3%) M (p<0.76), tumor size was 14.13 mm (range 0.5-80) , it was 13.97 mm (range 1-80) in F vs 14.62 (range 0.5-70) in M (p<0.42, association with thyroiditis was observed in 157 cases, in 132 (27%) F vs 25 (15%) M (p<0.001), BRAF – V600E mutation was identified in 143 (29%) F vs 52 (30.7%) M (p<0.849).
We revised the follow up in 395 cases. The mean time of follow up was 37 months (range 1-343) in F vs 45 months (range 4-156) in M, 251 (88%) F underwent I131radioiodinetherapy vs 91 (83%) M (p<0.74), the median dose was 132.63 mCi (range 50-500) in F vs 139.42 mCi (range 50-350) in M (p<0.27), the median time of follow up was 37 months in F and 45 months in M (p<0.24), the median value of Tireoglobulin (Tg) was 7 mU/L (range 0.1-485.3) in F vs 19.83 (range 0.1-593) in M (p<0.11), F was free of disease in 274 (96%) vs 102 (93.5%) M (p<0.64), 2 patients deceased , 1 was F (0.2%) vs 1 (1%)M (p<0.24).
Regarding the expression of estrogen receptors in thyroid tissue, 10 patients, with a median age of 48 years (range: 31-77) were analyzed. Mean follow-up time was 3 months (range 1-12). 10 thyroid glands specimens have been examined using immunohistochemical assays with ERs antibodies. We did not find any significant difference in the incidences of positive staining for E2 between the two groups.
There was no expression of antibodies in non-neoplastic cells or in adjacent tissues.
In conclusion, the identification of mechanisms of carcinogenesis of PTC in women vs men is a really important and innovative step for the study of thyroid cancer.
The estrogen hormones may play an important role as a promoting factor in the development of PTC. The role of estrogen in the progress of PTC, once identified the precise mechanisms and steps of tumorigenesis, could open up areas, as in breast cancer, of developing potential new medical antireceptorial therapies to prevent and treat thyroid malignancies. This indication needs further study

Abstract (italiano)

Il carcinoma papillare della tiroide (PTC) è il più frequente tipo di cancro differenziato della tiroide, e rappresenta circa l'80% dei casi. Esso ha un’incidenza di circa tre volte maggiore nelle donne rispetto agli uomini e rappresenta il settimo cancro per frequenza nella donna mentre nell’uomo esso è al quindicesimo posto. Tale aumento di incidenza esiste solo durante l’età fertile, difatti dopo gli 80 anni di età, non si evidenzia più una differenza per quanto riguarda l’incidenza di questo tumore tiroideo tra i due sessi.
Recentemente è stato ipotizzato un ruolo degli ormoni sessuali, in particolare degli estrogeni, nell’induzione della tumorigenesi per lo sviluppo del cancro tiroideo, ma i meccanismi che regolano questi eventi non sono ancora stati ben identificati [1-6].
I recettori degli steroidi sono caratterizzati da un'elevata affinità e specificità in rapporto ai loro leganti. Il recettore dell'estrogeno umano (ER) è una proteina dimerica con peso molecolare di 65 kDa, localizzata principalmente sulla membrana del nucleo cellulare e appartenente a una classe di proteine attivatrici, che stimolano cioè la trascrizione legandosi a elementi specifici del DNA, detti anche elementi di risposta ormonale. Legandosi con l'estrogeno, il recettore ER è indotto a stimolare la trascrizione genica; per questo motivo è noto anche come fattore enhancer inducibile.
Studi storici hanno dimostrato che lo stato di ER è correlato direttamente con la prognosi (ad es. positivamente nel tumore della mammella invasivo ben differenziato) e alla risposta alla terapia anti-ormonale, ad es., tamoxifen.
È stato riscontrato che gli estrogeni sono principalmente concentrati negli organi bersaglio degli estrogeni di animali e nei tumori umani della mammella ed è ben documentato che gli effetti mitogenici dell'estrogeno sono mediati dall'ER. Indagini eseguite riguardo i meccanismi biologici per la crescita del tumore della mammella hanno dimostrato che la velocità della crescita dipende dalla presenza di estrogeni o progesterone o di entrambi in gran parte dei tumori della mammella. Pertanto, lo stato del recettore estrogeno nei carcinomi mammari è considerato uno strumento di previsione convalidato e un fattore predittivo per il trattamento della paziente con terapia anti-ormonale.
Lo scopo del nostro studio è stato quello di analizzare i pazienti sottoposti a chirurgia per PTC e confrontare le femmine (F) vs i maschi (M) per quanto riguarda le variabili cliniche ed istopatologiche per determinare se, come nel carcinoma mammario, vi sono delle differenze significative e vi sia effettivamente un ruolo degli estrogeni nella patogenesi del PTC.
In una piccola quota di pazienti è stata valutata la presenza di recettori per gli estrogeni sul pezzo operatorio per poter eventualmente identificare anche la possibilità di una terapia medica oncologica mirata per questo tipo di tumore. La ricerca di tali recettori è stata fatta per valutare quali recettori erano presenti e in che quantità e per determinare se la presenza o l’assenza di questi determinava un impatto sulla prognosi.
Abbiamo considerato 658 pazienti sottoposti a tiroidectomia per PTC dal 2007 al 2011 presso la Clinica Chirurgica II dell’Università degli Studi di Padova e l’Unità Operativa Complessa di Chirurgia Generale dell’Università degli Studi di Trieste. Abbiamo analizzato retrospettivamente i dati clinici ed istopatologici e abbiamo confrontato F vs M per quanto riguarda le seguenti variabili: età, estensione della chirurgia, tipo di dissezione linfonodale, stadi azione sec. TNM, mono/plurifocalità, l’associazione con tiroidite cronica, la presenza di mutazione BRAF ed il follow-up. Inoltre nelle donne sono state analizzate, l’età del menarca e della menopausa, il numero e l’età delle gravidanze, le eventuali interruzioni di gravidanza e la terapia estro-progestinica. Un valore di p inferiore a 0.05 è stato considerato statisticamente significativo.
Di 10 pazienti selezionati abbiamo analizzato il livello di estrogeni nel siero perioperatorio e l’espressione dei recettori ER-alpha ed ER-beta mediante studi immunoistochimici per la rilevazione semi-quantitativa del recettore dell’estrogeno umano in sezioni di tessuto fissate in formalina, incluse in paraffina di tumore della tiroide.
Questi 10 pazienti, tutte femmine, sono stati suddivisi in due gruppi da cinque in base all’età maggiore o minore di 40 anni e questi due gruppi sono stati confrontati tra di loro.
Confrontando F vs M abbiamo riscontrato una differenza statisticamente significativa per quanto riguarda il sesso, difatti le donne sono state il 74% mentre il sesso maschile ha rappresentato il 26% dei casi (p < 0,015) e l’associazione con tiroidite cronica autoimmune più frequente nelle donne.
La necessità di eseguire una dissezione linfonodale laterocervicale è stata maggiore nel sesso maschile, mentre non è stata riscontrata differenza statisticamente significativa riguardo il tasso di recidiva tra i due sessi.
Per quel che concerne lo studio del profilo ormonale nelle donne abbiamo riscontrato che uno stadio relativamente più avanzato era correlato con un menarca precoce, età più avanzata della prima gravidanza e menopausa tardiva.
Le femmine sono state 489 (74%) vs 169 maschi (26%) (p < 0,015), l'età media è stata di 46 anni (range 11-86) nelle F vs 46 anni (range 11-83) nei M (p < 0,44). La tiroidectomia totale è stata effettuata in 474 F (97%) mentre è stata effettuata in 161 M (95%) (p < 0,72). La dissezione linfonodale è stata realizzata in 387 (79%) F vs 132 (78%) M (p < 0,99), La linfoadenectomia del compartimento centrale è stata effettuata in 340 (88%) F vs 94 (71%) M (p < 0,75) mentre la dissezione laterocervicale è stata eseguita in 47 (12%) F vs 38 (29%) M (p < 0,011).
Per quanto concerne la stadiazione: 315 (64%) F vs 87 (51,5%) M (p < 0,19) presentavano uno stadio I di neoplasia, 15 (3%) F vs 4 (2,5%) M (p < 0,51) uno stadio II, 126 (26%) F vs 54 (32%) M (p < 0,24) uno stadio III mentre 33 (7%) F vs 24 (14%) M (p < 0.22) avevano uno stadio IV.
Il tumore era monofocale in 279 (57%) vs F 89 (52,7%) M (p < 0,64), mentre era plurifocale in 210 (43%) F vs 80 (47,3%) M (p < 0,76).
L'associazione con tiroidite cronica autoimmune era presente in 132 F (27%) e 25 M (15%) (p < 0,001). Per quanto riguarda la mutazione BRAF, la mutazione V600E è stata identificata in 143 (29%) F vs 52 (30,7%) M (p < 0.84).
Il follow-up è stato possibile in 395 casi. Il tempo medio di follow-up è stato di 37 mesi (range 1-343) nelle femmine rispetto a 45 mesi (range 4-156) nei maschi(p < 0,24). 251 F (88%) si sono sottoposte a I131radioiodioterapia vs 91 M (83%) (p < 0,74) e la dose media è stata di 132.63 mCi (range 50-500) nelle F vs 139.42 mCi (range 50-350) nei M (p < 0,27).
I livelli medi di Tireoglobulina (Tg) erano 7 mU/L (range 0,1-485.3) nelle F vs 19.83 (range 0,1-593) nei M (p < 0,11). 274 F (96%) vs 102 M (93.5%) erano libere da malattia al follow-up (p < 0,64). Abbiamo riscontrato una differenza statisticamente significativa per quel che riguarda il numero di pazienti, la dissezione linfonodale laterocervicale e l'associazione con tiroidite cronica autoimmune.
Riguardo all’espressione dei recettori per gli estrogeni sul pezzo operatorio, sono stati studiati 10 pazienti, con un’età media di 48 anni (range: 31-77) Il follow-up medio è stato di 3 mesi (range 1-12). 10 preparati chirurgici tiroidei sono stati analizzati con tecnica immunoistochimica e sono stati testati gli anticorpi per gli estrogeni alpha e beta.
I recettori per gli estragoni erano presenti nella maggior parte del campione (80%) e non c’erano nel tessuto peritumorale.
In conclusione, l’identificazione dei meccanismi di carcinogenesi del PTC nella donna rispetto all’uomo rappresenta un passo veramente importante ed innovativo per lo studio del carcinoma tiroideo, in particolare il ruolo degli estrogeni nello sviluppo del PTC, una volta identificati i precisi meccanismi e steps della tumori genesi, potrebbe aprire la strada, come nel cancro mammario, per una potenziale nuova terapia medica antirecettoriale

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Tipo di EPrint:Tesi di dottorato
Relatore:Pelizzo, Maria Rosa
Dottorato (corsi e scuole):Ciclo 26 > Scuole 26 > ONCOLOGIA E ONCOLOGIA CHIRURGICA
Data di deposito della tesi:22 Gennaio 2014
Anno di Pubblicazione:22 Gennaio 2014
Parole chiave (italiano / inglese):papillary thyroid cancer; gender disparity; incidence; hormonal factors/ cancpo papillifero tiroide; studio di genere; fattori ormonali
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/18 Chirurgia generale
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze Chirurgiche Oncologiche e Gastroenterologiche
Codice ID:6308
Depositato il:12 Nov 2014 12:25
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