| Abstract | Cilj studije: Analizirati izražaj PD-L1 i IMP3 u nesitnostaničnom karcinomu pluća (NSCLC) i usporediti ga s odgovorom tumorskog imunog mikrookoliša (TIM), kliničko-patološkim parametrima, vremenom bez povrata bolesti (DFS) i općim preživljenjem (OS). Materijal i metode: Uzorak uključuje 76 ispitanika i 32 ispitanice koji su zbog NSCLC-a bili podvrgnuti operaciji u KBC-u Split od 2012. do 2018. godine i nisu liječeni tirozin-kinaznim inhibitorima niti imunoterapijom. Iz parafinskih blokova tumorskog tkiva izrezani su preparati i strojno imunohistokemijski obojeni na PD-L1 (22C3, DAKO, Glostrup, Danska) i IMP3 (DAKO). Preparati su analizirani na svjetlosnom mikroskopu Olympus BX46. Izražaj PD-L1 je vrednovan kao postotak pozitivnih tumorskih stanica među zloćudnim stanicama, a izražaj IMP3 izračunan kao H-skor. Rezultati: Srednja dob muškaraca bila je 66, a žena 64 godine. Adenokarcinom je dijagnosticiran u 68 (63 %), planocelularni karcinom u 35 (32 %) i NSCLC drukčije nespecificiran u pet (5 %) slučajeva. Ispitanici, njih 50 (47,2 %) bilo je je u I., njih 31 (29,2 %) u II. i njih 25 (23,6 %) u III. stadiju bolesti. Metastatsku nodalnu bolest imalo je 38 (36 %) ispitanika, njih 18 kao N1 i njih 20 kao N2. Ispitanici su praćeni do 1. 01. 2019. godine. Prosječno vrijeme bez pojave bolesti bilo je 17 mjeseci, medijan preživljenja za muškarce bio je 44, a za žene 62 mjeseca. Spol, dob i histološki tip nisu povezani s izražajem PD-L1 (svi p > 0,05). Podtipovi adenokarcinoma povezani su s izražajem PD-L1 (p = 0,01) tako da je papilarni podtip 4,3 puta češći među PD-L1 negativnim, a solidni podtip 1,9 puta češći među PD-L1 pozitivnim slučajevima. Odgovor TIM-a bio je jak u 19 NSCLC-a, slab u 36 i odsutan u 53 slučaja. Medijan izražaja PD-L1 povezan je s TIM-om (p = 0,039). Izražaj PD-L1 nije povezan s DFS-om ni s OS-om (p = 0,643). Ispitanici s jakim upali sličnim odgovorom u TIM-u imaju 12 mjeseci duži OS nego ispitanici s odsutnim/slabim imunim odgovorom (LR = 2,8; p = 0,132). Izražaj IMP3 povezan je sa solidnim podtipom (p = 0,02) i granično povezan s pozitivnim nodalnim statusom (p = 0,051). Zaključak: Jak upali sličan odgovor u TIM-u povezan je s pozitivnim izražajem PD-L1 u tumoru, a pozitivan izražaj IMP3 u primarnom tumoru s postojanjem nodalnih metastaza. Limfovaskularna invazija značajno smanjuje DFS i OS, a solidni podtip adenokarcinoma povezan je s kraćim OS-om. |
| Abstract (english) | Aim of the study: to analyze the expression of PD-L1 and IMP3 in non-small cell lung cancer (NSCLC) and compare it with the response of the tumor immune microenvironment (TIM), clinico-pathological parameters, disease-free survival (DFS) and overall survival (OS). Material and methods: The sample includes 76 males and 32 females who underwent surgery for NSCLC at University hospital Split in the period 2012-2018 and did not receive tyrosine kinase inhibitor therapy or immunotherapy at all. Slides were cut from paraffin blocks of tumor tissue and immunohistochemically stained for PD-L1 (22C3, DAKO, Glostrup, Danska) and IMP3 (DAKO). The histologic slides were analyzed on an Olympus BX46 light microscope. PD-L1 expression was evaluated as the percentage of positive tumor cells among malignant cells, and IMP3 expression was calculated as H score. Results: The median age of men was 66 years, and women 64 years. Adenocarcinoma was diagnosed in 68 (63%), squamous cell carcinoma in 35 (32%) and NSCLC not otherwise specified in 5 (5%) cases. 50 (47.2%) patients were in stage I, 31 (29.2%) in stage II and 25 (23.6%) in stage III of the disease. 38 (36%) patients had metastatic nodal disease, 18 as N1 and 20 as N2. Follow up was until January 1, 2019. The average DFS was 17 months, and the median survival for men was 44 and for women 62 months. Gender, age and histological type were not associated with PD-L1 expression (all p > 0.05). Adenocarcinoma subtypes were associated with PD-L1 expression (p = 0.01) such that the papillary subtype was 4.3 times more frequent among PD-L1 negative and the solid subtype 1.9 times more frequent among PD-L1 positive cases. TIM response was strong in 19 NSCLC, weak in 36 and absent in 53 cases. Median expression of PD-L1 positively correlated with strong, inflammation- like TIM response (p = 0.039). PD-L1 expression was not associated with DFS and OS (p = 0.643). Patients with a strong TIM response had a 12-month longer OS than patients with an absent/weak response (LR = 2.8; p = 0.132). IMP3 expression was associated with planocellular carcinoma (p= 0,05), solid subtype of adenocarcinoma (p=0.02) and borderline associated with positive nodal status (p=0.051). Conclusion: A strong inflammatory-like response in TIM is associated with positive expression of PD-L1 in the tumor, and positive expression of IMP3 in the primary tumor with the presence of nodal metastasis. Lymphovascular invasion significantly reduces DFS and OS, and the solid adenocarcinoma subtype is associated with shorter OS. |
