Imunohistokemijska izraženost i prognostička vrijednost proteina nm23-H1 i COX-2 u papilarnom karcinomu štitnjače

Milković Periša, Marija (2011) Imunohistokemijska izraženost i prognostička vrijednost proteina nm23-H1 i COX-2 u papilarnom karcinomu štitnjače. PhD thesis, Sveučilište u Zagrebu.

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Abstract

Papillary thyroid carcinoma is an epithelial tumor that frequently affects young women. Although it has an excellent prognosis, there is a small group of patients who present a tumor with a more aggressive behavior. So far, the research directed to the specific age and gender groups, histological variants, tumor diameter, intraglandular spread and the presence of metastases have not succeeded in definitely identifying the group of tumors with aggressive behavior, although some studies have shown the age, tumor diameter, tumor local invasiveness, metastases to regional lymph nodes and distant metastasis as independent prognostic factors. The nm23 gene belongs to a group of tumor suppressors, whereas COX-2 is an enzyme, expressed at inflammation sites and in many different carcinomas. Both proteins have been separately studied in papillary thyroid cancer, and the obtained results were contradictory. However, it has been shown in vitro that COX-2 transcription depends on nm23-H1 expression. The hypothesis of this study was based on importance of nm23-H1 and COX-2 expression in predicting a smaller group of patients with a biologically more aggressive primary tumor at the time of diagnosis. A total of 130 samples of papillary thyroid carcinoma tissue was analyzed in this study. The following parameters were analyzed: the tumor sub-type, the presence of lymphocyte inflammatory infiltrate, intraglandular dissemination, benign changes in the thyroid gland and regional metastases in lymph nodes. For detection of nm23-H1 and COX-2, immunohistochemical staining have been performed with highly specific monoclonal antibodies. Immunohistochemical analysis results show middle-strong and very positive staining for both proteins, in majority of tumors. The expression of COX-2 was always joined with nm23-H1 positivity (P<0,001). The expression of nm23-H1 and COX-2 is not related to the patient's age or gender, tumor diameter, intraglandular dissemination of the tumor and the presence of metastasis in regional lymph nodes. The nm23-H1 median expression is significantly higher in the classical and follicular histological variant of papillary carcinoma, compared to other histological variants (P=0,044). On the other hand, the median COX-2 expression is significantly higher in the follicular histological variant, and decreased in the diffuse-sclerosing variant (P=0,014). The presence of lymphocyte inflammatory infiltrate in the tumor is connected to the presence of thyroiditis in the surrounding, non-tumorous tissue of the thyroid gland (P<0,001), but it does not relate to the expression of nm23-H1 and COX-2 in the tumorous tissue. Finaly, COX-2 expression in papillary microcarcinoma is related to the metastases to regional lymph nodes (P=0,017). The results of this research show that there is relation in the expression of nm23-H1 and COX-2 in the papillary carcinoma of the thyroid gland, particularly with respect to histological sub-variants. Although, their expression does not help in identifying the group of more aggressive papillary carcinomas, it could help in identifying the group of more aggressive papillary thyroid microcarcinoma.

Abstract in Croatian

Papilarni karcinom štitnjače je epitelni tumor koji se najčešće javlja u mlađih žena. Iako ima dobru prognozu, postoji manja skupina bolesnika s tumorom agresivnijeg ponašanja. Dosadašnjim se istraživanjima nije uspjela izdvojiti agresivnija skupina tumora, iako je pokazano da su dob, veličina tumora, lokalna invazivnost tumora, metastaze u regionalnim limfnim čvorovima i udaljene metastaze, u ovim tumorima, neovisni prognostički čimbenici. Gen nm23 pripada skupini tumor supresorskih gena, a COX-2 je enzim izražen na mjestima upale i u različitim vrstama karcinoma. Oba su proteina odvojeno istraživana u tumorima štitnjače, a rezultati su, prema dosadašnjim studijama, oprečni. Njihova međusobna povezanost pronađena je u stanicama inficiranim virusom EBV u kojima je transkripcija COX-2 bila potaknuta signalnim putem NFκB, koji je ovisio o ispoljenosti nm23-H1. U ovo su istraživanje bili uključeni uzorci tkiva papilarnog karcinoma dobiveni od 130 bolesnika, za koje su bile poznate dob, spol i veličina tumora. Uzorci su bili analizirani standardnom patohistološkom metodom kako bi se odredili slijedeći parametri: histološki podtip tumora, prisutnost limfocitnog upalnog infiltrata, prisutnost širenja tumora u okolno tkivo štitnjače, prisutnost dobroćudnih promjena u štitnjači, prisutnost metastaza u limfnim čvorovima. Metodom imunohistokemije je određena razina izraženosti proteina nm23-H1 i COX-2, kako bi se provjerila slijedeća hipoteza u skupini bolesnika s papilarnim karcinomom, kao i u skupini bolesnika s papilarnim mikrokarcinomom štitnjače, prisutnost enzima COX-2 i tumor supresorskog proteina nm23-H1 izdvojit će manju skupinu bolesnika s biološki agresivnijim primarnim tumorom, u vrijeme postavljanja dijagnoze. U većini je tumora reakcija izraženosti nm23-H1 i COX-2 srednje i jako pozitivna. U tumorima u kojima je izražen COX-2, izražen je i nm23-H1 (P<0,001). Izraženost nm23-H1 i COX-2 nije povezana s dobi i spolom bolesnika, veličinom tumora te širenjem tumora u okolno tkivo žlijezde i prisutnosti metastaza u regionalnim limfnim čvorovima. Medijan izraženost nm23-H1 značajno je veći u klasičnom i folikularnom histološkom podtipu papilarnog karcinoma u odnosu na ostale histološke podtipove (P=0,044), a medijan izraženosti COX-2 značajno je veći u folikularnom histološkom podtipu, u odnosu na difuzno-sklerozirajući podtip (P=0,014). Prisutnost limfocitnog upalnog infiltrata u tumoru povezana je s prisutnosti tireoiditisa u okolnom tkivu štitnjače (P<0,001), ali nije povezana s izraženošću nm23-H1 i COX-2 u tkivu tumora. Međutim, izraženost COX-2 u papilarnom mikrokarcinomu povezana je s prisutnošću metastaza u regionalnim limfnim čvorovima (P=0,017). Rezultati ovoga istraživanja ukazuju da postoji međusobna povezanost u izraženosti nm23-H1 i COX-2 u papilarnom karcinomu štitnjače. Iako razina njihove izraženosti ne pomaže u izdvajanju skupine agresivnijih papilarnih karcinoma, mogla bi biti korisna, u izdvajanju agresivnije skupine papilarnih mikrokarcinoma štitnjače.

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