1. LUNG ADENOCARCINOMAS. CLINICOPATHOLOGICAL STUDY WITH RESPECT TO THE UPCOMING NEW CLASSIFICATION AND EGFR-KRAS MUTATION ANALYSIS IMPLICATIONS. First author: Andone Sebastian Co-author: Roman Adina Coordinator: Mezei Tibor, MD

2. Introduction The incidence of lung adenocarcinoma has increased significantly –US > 50% [1] Adenocarcinoma surpassed squamous cell carcinoma in the last few years Recent histopathological and genetic studies provided an extended pathway to research [1]Motoi, Noriko, et al. "Lung adenocarcinoma: modification of the 2004 WHO[..]." The American journal of surgical pathology 32.6 (2008): 810-827.

3. 2004 WHO Classifcation Introduction Travis et al “International Association for the study of Lung Cancer[..]” Journal of Thoracic Oncology, Volume 6, Number 2 February 2011 246-247 New proposed classification (WHO 2015)

4. Current histological types of adenocarcinomas –Mixed subtype –Acinar –Papillary –Solid –Brochioloalveolar Immunohistochemical markers: –CK7, TTF1, Napsin Introduction

5. Macroscopic aspects of adenocarcinoma

6. Microscopic aspects of adenocarcinoma [1][2] [3][4] [1] – Acinar [3] – Papillary [2] – Bronchioloalveolar [4] - Solid

7. Immunohistochemistry stains [1][2] [3][4] [1] – TTF1 [3] – CK7 [2] – TTF1 [4] - CEA

8. Main purpose: –To review and study adenocarcinoma lung tumors incidence and clinicopathological features Specific purposes: –Obtaining a theoretical basis of EGFR-KRAS mutation implications and the importance of their biologic and therapeutic relevance Objective

9. 140 cases registered at the Pathology Department in the 2003-2013 period Evaluation of clinical factors with prognostic value in the diagnosis of adenocarcinoma –Age, gender, tumor size, pathological stage, extent of resection, histological subtype Evaluation of parameters that may suggest possible EGFR or KRAS mutations: –Necrosis, atypical glandular differentiation, mucin growth patterns Material and method

10. We included the data into two groups: –Low-grade adenocarcinoma –High-grade adenocarcinoma Age and sex distribution Maximal size Location/focality EGFR-KRAS histopathological features Results

11. Data showed an higher incidence in men (71.40%). Women diagnosed with adenocarcinoma 24,6% (2003-2008)  32% (2008-2013) Results

12. Adenocarcinoma Squamous cell carcinoma

13. Increased number of women diagnosed with adenocarcinoma than squamous cell carcinoma in the same period. Mean age of diagnosis of adenocarcinoma is 59 years. Age statistical analysis between high-grade- low- grade adenocarcinoma : p=0.18 Results

14. Maximal size analysis was performed according to histological grade and data distribution to high-grade and low- grade tumors High grade tumors present a higher maximal size distribution (p=0.02) Results

15. Low grade tumors High grade tumors

16. Results

17. Specific EGFR-KRAS histopathological features: Necrosis (70%) Atypical glandular differentiation (35%) Mucin growth patterns (10%) Histological type: 90% of tumors were mixed subtype Results

18. Possible explanations regarding the increased incidence of adenocarcinoma –Increased incidence of smoking in women –Usage of filter cigarettes [1] –Increased incidence among young adults [2] Discussions [1] Hidemi Ito et al “Nonfilter and filter cigarette consumption [..]” International Journal of Cancer, Volume 128 issue 8, pages 1918–1928, 15 April 2011 [2]Lung Cancer In Young Adults. Bourke W, Milstein D, Giura R, et al.Chest 1992;102(6):1723-1729.

19. Patients with EGFR mutation were most likely to be never smokers and present stage I disease and had a 90% 3 year-overall survival. Patients with KRAS mutation tumors were more likely to be former/current smokers, present with locally advanced disease and have a 65% 3 year-overall survival. Response to treatment – EGFR mutation – therapy with Tyrosin Kinaze inhibitors – (Erlotininb, Geftinib) In our country, the main therapy includes monoclonal antibodies treatment (Trastuzumab, Bevacizumab), which has proved its efficiency, but is surpassed nowadays in the latest studies by the efficiency of TKI of NSCLC. Discussions Finberg, Karin E., et al. "Mucinous Differentiation Correlates [..]." The Journal of Molecular Diagnostics 9.3 (2007): 320-326.

20. Basic conclusions –Increased incidence of diagnosis in women [1] –The incidence of diagnosis in young adults –The upcoming (?) 2015 WHO classification and its possible correlation with genetic mutations –The importance of testing for EGFR-KRAS mutation Conclusions [1] Ronald G.Vincent et al “ The changing histopathology of lung cancer[..]” Cancer, volume 39, Isssue 4 pages 1647-1653 June 2006

21. Novelty and limitations –Complete analysis of clinicopathological features –Statistical analysis based on histological grade comparison –Recent studies evaluation –The limitations of immunohistochemical complete studies –The limitations concerning gene mutation analysis –National Cancer Registry limitations Conclusions