Unit:
Τομέας ΚλινικοεργαστηριακόςLibrary of the School of Health Sciences
Author:
Sofopoulos Michail
Dissertation committee:
Σπηλιοπούλου Χ. Καθηγήτρια, Ιατρική, ΕΚΠΑ
Μαρκόπουλος Χ, Καθηγητής, Ιατρική, ΕΚΠΑ
Καβαντζάς Ν., Καθηγητής, Ιατρική, ΕΚΠΑ
Λάζαρης Α., Καθηγητής, Ιατρική, ΕΚΠΑ
Βλαχοδημητρόπουλος Δ, Αν. Καθηγητής, Ιατρική, ΕΚΠΑ
Νόννη Α, Αν. Καθηγήτρια, Ιατρική, ΕΚΠΑ
Γούτας Ν, Αν. Καθηγητής, Ιατρική, ΕΚΠΑ
Original Title:
Στοιχεία του μικροπεριβάλλοντος στον καρκίνο του μαστού ως προγνωστικός δείκτης
Translated title:
Elements in breast cancer microenviroment used as prognostic index
Summary:
Background: Tumors and their surrounding area represent spatially organized “ecosystems”, where tumor cells and the immune contextures of the different compartments are in a dynamic interplay. Tumor immune-cell infiltration is progressively becoming an important aspect for tumor characterization and clinical outcome prediction of cancer patients. Little has been done to evaluate the importance of diverse compartmental immune cell distribution in breast cancer (BCa) nor to assess the presence and number of Tertirary Lymphoid Structures that may surround each tumor. The latter are lymph-node-like structures sharing architectural and functional characteristics with secondary lymphoid organs and are often detected in the tumor microenvironment. Their presence has been associated with controversial clinical outcomes. The scope of this thesis is to clarify their relation with prognosis in BCa patients alone and in combination with tumoral immune infiltrates.
Methods: Formalin-fixed, paraffin-embedded tumor tissue samples from 167 BCa patients, with invasive ductal, non-metastatic BCa, not treated with neoadjuvant chemotherapy, have been used to detect and quantify the presence immune cell infiltrates in the diverse tumor compartments (Tumor center-TC,Infiltrative margin -IM). Tumor tissue was stained with (CD4,CD8,CD163,FoxP3) immunostains and photographed in multiple locations inside the tumor center and along its infiltrative margin. TLS assessment was also performed. The latter were identified morphologically as ovoid lymphocytic aggregates presenting a germinal center and/or high endothelial venules. Subsequently those were counted and furthermore characterized as adjacent(aTLS, within the tumor IM) or as distal(dTLS,≤5mm from the IM within the non-neoplastic tissue). Clinical follow-up was available for 112 of these patients. The cellular densities of CD8+ and CD163+ were calculated by means of immunohistochemical stains, microphotographs and image analysis software (ImageJ - particle analysis). The presence and number of TLS was performed mainly in H&E slides with the occasional auxiliary use of immunohistochemical stains in ambiguous cases. Statistical analysis was performed with IBM SPSS Statistics 24.
Results: The results indicated that the combined assessment of CD8+ and CD163+ immune cell densities infiltrating diverse tumor compartments (TC and IM) may enhance the prognostic accuracy of disease progress (DFS and OS). The presence of increased CD8+ cellular densities inside the tumor center and decreased along the infiltrative border and/or the decreased cellular densities of CD163+ in tumor center and increased in periphery seem to be related with favorable prognosis whilst the opposite immune cell distributions with unfavorable prognosis. Regarding the assessment of peritumoral TLS, their absence was associated with longer DFS and OS. Moreover, not only the presence of peritumoral TLS, but also their density has been proven to be prognostically crucial, since patients with numerous peritumoral TLS exhibited worst DFS and OS. By combining quantitative peritumoral TLS measurements with the differential combined immunological cellular densities of CD8+ and CD163+ in the diverse cellular compartments (TC and IM), two immunological signatures with reinforced prognostic significance (RFCIS&RUCIS) were created which offered increased prognostic significance.
Conclusions: The results of the current thesis demonstrate for the first time an association between spatial differential densities of intratumoral immune infiltrates with peritumoral TLS and clinical outcomes which seems to influence DFS and OS. The observations further support the existence and importance of a dynamic interplay between the immune cells within the tumor microenvironment (TC,IM) and its surrounding counterpart (TLS).
Main subject category:
Health Sciences
Keywords:
Breast, Cancer, Microenviroment, Inflammation, TLS
Number of references:
132
