Title Prognostička vrijednost i međuodnos osteopontina i morfologije invazivne tumorske fronte u karcinomu pločastih stanica usne šupljine
Title (english) Prognostic value and relationship between osteopontin expression and morphology of invasive tumor front in squamous cell carcinoma of oral cavity
Author Manuela Avirović
Mentor Ksenija Lučin (mentor)
Committee member Mirna Juretić (član povjerenstva)
Committee member Spomenka Manojlović (član povjerenstva) MBZ: 32323
Committee member Nives Jonjić (član povjerenstva)
Granter University of Rijeka Faculty of Medicine (Department of General Pathology and Pathological Anatomy) Rijeka
Defense date and country 2014, Croatia
Scientific / art field, discipline and subdiscipline BIOMEDICINE AND HEALTHCARE Clinical Medical Sciences Pathology
Universal decimal classification (UDC ) 616 - Pathology. Clinical medicine
Thesaurus (MESH - Medical Subject Headings )
Carcinoma, Squamous Cell
Mouth Neoplasms
Osteopontin
Tissue Array Analysis
Abstract Ciljevi istraživanja: Karcinom pločastih stanica usne šupljine (KPSUŠ) peti je po učestalosti među zloćudnim tumorima, karakteriziran visokom učestalošću lokoregionalnog povrata bolesti. Budući da standardni prognostički pokazatelji ne daju pouzdane informacije o biološkom ponašanju tumora i mogućnosti povrata bolesti traga se za novim markerima koji bi mogli imati prognostičku i terapijsku vrijednost. Osteopontin (OPN) je multifunkcionalni protein koji je nedavno predložen kao prognostički marker u više tipova tumora. OPN sudjeluje u interakciji tumorskih stanica i njihovog mikrookoliša koja igra ključnu ulogu u progresiji i metastaziraju tumora i odražava se na morfologiju tumora u području invazivne tumorske fronte. Tumoru pridruženi makrofagi smatraju se ključnom sastavnicom tumorskog mikrookoliša koja može imati različit utjecaj na rast i metastaziranje tumora.
Cilj našeg istraživanja bio je utvrditi da li povećana ekspresija OPN-a ima ulogu u progresiji KPSUŠ-a te da li je povezana s morfologijom, odnosno gradusom invazivne tumorske fronte (GITF-om). Također, željeli smo ispitati prognostičku vrijednost sadržaja makrofaga u tumorskom mikrookolišu te njegov odnos prema ekspresiji osteopontina.
Ispitanici i metode: U studiju je uključeno 86 bolesnika kojima je u periodu od 2000.-2007. godine dijagnosticiran KPSUŠ na Klinici za maksilofacijalnu i oralnu kirurgiju, KBC-a Rijeka. Tkivne mikroaree tumora obojane su imunohistokemijskom metodom pomoću protutijela koja prepoznaju OPN, Ki67 marker proliferacije te CD68 marker makrofaga i analizirane uz pomoć računalnog programa. Ekspresija osteopontina i sadržaj makrofaga u tumoru uspoređeni su sa standardnim prognostičkim parametrima i preživljavanjem bolesnika te s Ki67 proliferacijskim indeksom. Na cjelovitim histološkim rezovima obojanim s hemalaun-eozinom određen je GITF i uspoređen s kliničkopatološkim parametrima i ekspresijom osteopontina u tumoru.
Rezultati: Ekspresija OPN-a u tumorskim stanicama (t-OPN) značajno je viša u odnosu na epitel nepromijenjene sluznice (p<0.001). Porast ekspresije t-OPN-a praćen je porastom ekspresije OPN-a u stromalnom odjeljku tumora (s-OPN) (p=0.023) te udružen s višim N stadijem (p=0.045) i TNM stadijem (p=0.033). Viši GITF udružen je s N stadijem (p=0.006) i TNM stadijem (p=0.025) te s višom ekspresijom t-OPN-a u površinskom dijelu tumora (p=0.038). U univarijatnoj analizi viša ekspresija t-OPN-a (p=0.022) i viši GITF (p=0.003) udruženi su s kraćim preživljenjem bolesnika. U multivarijatnoj analizi usporedbom sa standardnim prognostičkim pokazateljima ekspresija t-OPN-a se pokazala nezavisnim prediktivnim čimbenikom preživljenja (p=0.048). Uključivanjem GITF-a u multivarijatnu analizu ekspresija t-OPN-a gubi status nezavisnog prediktivnog čimbenika (p=0.085), dok ga GITF pokazuje (p<0.001). Ekspresija t-OPN-a nije bila udružena s tradicionalnim histološkim gradusom (p=0.260), proliferacijskim indeksom (p=0.145) niti sa sadržajem makrofaga u tumoru (p=0.904). Ekspresija s-OPN-a i sadržaj makrofaga u tumoru nisu bili udruženi s prognostičkim parametrima preživljenjem bolesnika. Bolesnici s visokom ekspresijom t-OPN-a i visokim sadržajem makrofaga u tumoru živjeli su značajno kraće u odnosu na one s niskim pojedinačnim ili oba parametra (p=0.014).
Zaključak: Povećana ekspresija OPN-a kao pojedinačni parametar te udružena s visokim sadržajem makrofaga može poslužiti kao čimbenik predviđanja loše prognoze, odnosno kraćeg preživljavanja bolesnika s KPSUŠ-om. Gradus ITF-e također predviđa tijek bolesti i ima veću vrijednost u odnosu na tradicionalni histološki gradus. Određivanje ovih parametara u patohistološkoj dijagnostici karcinoma pločastih stanica usne šupljine omogućuje prepoznavanje skupine bolesnika s većim rizikom za povrat bolesti kojima bi koristile dodatne metode liječenja.
Abstract (english) Objectives: Squamous cell carcinoma of the oral cavity (SCCOC) is the fifth most common among malignant tumors, characterized by a high incidence of locoregional recurrence. Since the standard prognostic indicators do not provide reliable information on the biological behavior of the tumor and the possibility of recurrence, the search for new markers that may have prognostic and therapeutic value is needed. Osteopontin (OPN) is a multifunctional protein that has recently been proposed as a prognostic marker in multiple tumor types. It is involved in the interaction of tumor cells and their microenvironment, which plays a key role in the tumor progression and metastasis and is reflected in the morphology of the tumor in the area of invasive tumor front. Tumor associated macrophages are considered to be a key component of the tumor microenvironment, which can have a different impact on the growth and metastasis of tumors.
The aim of our study was to determine whether increased expression of osteopontin plays a role in the progression SCCOC's and whether it is related to the morphology of the invasive tumor front. Also, we wanted to examine the prognostic value of the macrophage content in the tumor microenvironment and its relationship to osteopontin expression.
Patients and Methods: The study included 86 patients that were surgically treated for SCCOC between 2000 and 2007 at the Department of Maxillofacial and Oral Surgery, Clinical Hospital Center Rijeka. Tumor microaree were stained by immunohistochemical methods using antibodies that recognize OPN, Ki67 proliferation marker, and CD68 macrophage marker, and analyzed by using a computer program. Expression of osteopontin and macrophage content in the tumor were compared with the standard prognostic parameters and survival of patients, as well as with the Ki67 proliferative index. The whole tumor-tissue sections, stained with hemalaun-eosin, were evaluated for the invasive tumor front grade (GITF) and compared with the clinicopathological parameters and osteopontin expression.
Results: The expression of OPN in tumor cells (t-OPN) was significantly higher compared to normal oral mucosa (p<0.001). Increase in the t-OPN expression was followed by the increased OPN expression in the stromal compartment of the tumor (s-OPN) (p=0.023), and associated with higher N stage (p=0.045), and TNM stage (p=0.033). Higher GITF was associated with higher N stage (p=0.006) and TNM stage (p=0.025), and a higher t-OPN expression in the superficial part of the tumor (p=0.038). In univariate analysis higher t-OPN expression (p=0.022) and a higher GITF (p=0.003) were associated with shorter survival of patients. In multivariate analysis, by comparing with standard prognostic factors, t-OPN expression was independent predictive factor for survival (p=0.048). When the GITF was included, t-OPN lost the status of an independent predictor (p=0.085), while GITF gained the status (p<0.001). Expression of t-OPN was not associated with traditional histological grade (p=0.260), Ki67 proliferative index (p=0.145) nor with the macrophage content in the tumor (p=0.904). Expression of the s-OPN and macrophage content in the tumor were not associated with prognostic parameters and survival of patients. Patients with combined high t-OPN expression and the high macrophage content in the tumor lived significantly shorter than those with low individual or both parameters (p=0.014).
Conclusion: Increased OPN expression as a single parameter or associated with a high macrophage content can serve as a predicting factor of poor prognosis, and shorter survival in patients with SCCOC. ITF grade also predicts the course of the disease and has a better prognostic value compared to traditional histological grade. Determination of these parameters in pathohistological diagnosis of squamous cell carcinoma of the oral cavity allows the identification of patients at high risk for relapse which would benefit from additional treatment methods.
Keywords
Karcinom pločastih stanica usne šupljine
Osteopontin
ekspresija
Invazivna tumorska fronta
morfologija
Stanični mikrookoliš tumora
Prognostička vrijednost
Keywords (english)
Oral carcinoma
squamous cell carcinoma
Osteopontin
expression
Invasive tumor front
morphology
Cellular tumor microenvironment
Prognostic value
Language croatian
URN:NBN urn:nbn:hr:184:338297
Study programme Title: Biomedicine Postgraduate (doctoral) study programme Study programme type: university Study level: postgraduate Academic / professional title: doktor/doktorica znanosti, područje biomedicine i zdravstvo (doktor/doktorica znanosti, područje biomedicine i zdravstvo)
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Created on 2016-03-01 16:41:45