Thymic Epithelial Tumors

Transcription

1 Thymic Epithelial Tumors Stefan Janik, M.D Vienna, December 12, 2016 Supervisor BERNHARD MOSER, MD, ASSOC. PROF.,PD, FEBTS HENDRIK JAN ANKERSMIT MD, UNIV. PROF.,PD, MBA

2 Introduction Thymic Epithelial Tumors (TETs) Thymomas, Thymic Carcinomas and Thymic Neuroendocrine Tumors Most common tumors (30-50%) in the anterior mediastinum in adults 1,2 1 Detterbeck FC, Parsons AM. Thymic tumors. Ann Thorac Surg. 2004;77(5): Venuta F, Anile M, Diso D, Vitolo D, Rendina EA, De Giacomo T, Francioni F, Coloni GF. Thymoma and thymic carcinoma. Eur J Cardiothorac Surg. 2010; 37(1):

3 Introduction Thymic Epithelial Tumors (TETs) Thymomas, Thymic Carcinomas and Thymic Neuroendocrine Tumors Most common tumors (30-50%) in the anterior mediastinum in adults 1,2 Incidence 1.3 to 3.2 per person-years 3,4 (15-20 cases MUV) Origin from thymic epithelial cells 3 Engels EA, Pfeiffer RM. Malignant thymoma in the United States: demographic patterns in incidence and associations with subsequent malignancies. Int J Cancer 2003; 105: de Jong WK, et al. Thymic epithelial tumours: a population-based study of the incidence, diagnostic procedures and therapy. Eur J Cancer. 2008; 44(1):

4 Introduction Thymic Epithelial Tumors (TETs) Thymomas, Thymic Carcinomas and Thymic Neuroendocrine Tumors Most common tumors (30-50%) in the anterior mediastinum in adults 1,2 Incidence 1.3 to 3.2 per person-years 3,4 (15-20 cases MUV) Origin from thymic epithelial cells Symptoms: paraneoplastic Myasthenia Gravis!!!, shortness in breath, palsy of laryngeal or phrenic nerve, chest pain, persisting coughing,... Paraneoplastic Myasthenia Gravis 5 unique association!!! 10-15% of myasthenic patients have TETs 30% of patients with TETs suffer from MG ¾ of MG patients show thymic pathologies (Thymic Hyperplasia!) 5 Marx A, et al. Thymoma and paraneoplastic myasthenia gravis. Autoimmunity. 2010; 43(5-6):

5 Regular Thymus Thymic Pathologies Benign Thymic Hyperplasia Malignant - TETs TTH FTH Thymomas, TC, TNET * GZ * Medulla

6 Introduction CHRISTIAN DOPPLER LABORATORY Classification of TETs: Thymoma, TC and TNET -> different oncologic behaviour o WHO Histological Classification System (A,AB,B1,B2,B3,...), TC and TNET o Masaoka Koga Staging (I,II,III,IV) Diagnostic: X-ray, CT, MRT, PET-CT Therapy: Surgery, (Radiotherapy, Chemotherapy)

7 Introduction Prognosis and Outcome CHRISTIAN DOPPLER LABORATORY Completeness of surgical resection (R0) WHO tumor subtype Masoaka Koga Stage 10-year Overall Survival 6 Stage I ~ 90 % ~ 90 % Stage II ~ 70 % ~ 78 % R0 Stage III ~ 55 % ~ 75 % Stage IVa ~ 35 % ~ 42 % Recurrences 10-30% even decades after radical tumor resection (R0) 7 6 Detterbeck F, Parsons AM. Management of Stage I and II Thymoma, Thorac Surg Clin Feb;21(1):59-67, vi-vii. 7 Kondo K, Yoshizawa K, Tsuyuguchi M, Kimura S, Sumitomo M, Morita J, Miyoshi T, Sakiyama S, Mukai K, Monden Y. WHO histologic classification is a prognostic indicator in thymoma. Ann Thorac Surg. 2004; 77(4):

8 Current Situation + Knowledge how to treat TETs + Knowledge about different subtypes of TETs and their clinical behaviour + How to achieve good survival rates BUT... - Pathogenesis is still unclear - No established risk factors - No established biomarkers for detection or oncologic follow up??? need to improve our understanding of the pathogenesis of TETs -> identify new promising molecules!!! Heat Shock Proteins!!!

9 6 Khalil AA., Kabapy NF., Deraz SF., et al. Heat shock proteins in oncology: diagnostic biomarkers or therapeutic targets? Biochem Biophys Acta (2011);1816: Garrido C., Brunet M., Didelot C., et al. Heat shock protein 27 and 70: anti-apoptotic proteins with tumorigenic properties. Cell Cycle (2006);5: Juhasz K., Lipp AM., Nimmervoll B., et al. The Complex Function of Hsp70 in Metastatic Cancer. Cancers (2014);6:42-66 Heat Shock Proteins CHRISTIAN DOPPLER LABORATORY Induced by different kind of stressors (heat, oxidative stress, hypoxia,...) Classified according to molecular weight HSP100, HSP90, HSP70, HSP60, HSP40 and small HSPs (HSP27) 6 HSP27 and 70 strongest inducable heat shock proteins 7 Main functions INTRACELLULAR 1. Molecular chaperones: protein folding, transport, homeostasis 2. Inhibition of apoptosis: extrinsic and intrinsic pathway EXTRACELLULAR extracellular danger signals -> chronic inflammatory environment 8 HSPs in cancer -> associated with tumor growth, resistance to chemotherapy, metastases and poor clinical outcome 6

10 Heat Shock Proteins in our working group (2) Elevated HSP27, HSP70 and HSP90 alpha in COPD (Hacker S et al.; Clin Lab. 2009) Increased HSP27 serum levels as a marker for incipient COPD (Ankersmit HJ et al.; Respiraton 2012)

11 Heat Shock Proteins in our working group (3) Elevated HSP27, HSP70 and HSP90 alpha in COPD (Hacker S et al.; Clin Lab. 2009) Increased HSP27 serum levels as a marker for incipient COPD (Ankersmit HJ et al.; Respiraton 2012) HSP27 as biomarker for the differentiation of patients with NSCLC and healthy controls (Zimmermann M et al.; Clin Lab. 2014) Discrimination of clinical stages in NSCLC patients by serum HSP27 and HSP70: a multi-institutional case-control study. (Zimmermann M et al.; Clin Chim Acta 2012)

12 Heat Shock Proteins in our working group (5) Elevated HSP27, HSP70 and HSP90 alpha in COPD (Hacker S et al.; Clin Lab. 2009) Increased HSP27 serum levels as a marker for incipient COPD (Ankersmit HJ et al.; Respiraton 2012) HSP27 as biomarker for the differentiation of patients with NSCLC and healthy controls (Zimmermann M et al.; Clin Lab. 2014) Discrimination of clinical stages in NSCLC patients by serum HSP27 and HSP70: a multi-institutional case-control study. (Zimmermann M et al.; Clin Chim Acta 2012) Stromal expression of HSP 27 is associated with worse clinical outcome in patients with colorectal cancer lung metastases. (Schweiger T et al.; PLoS One 2015)

13 HALLMARKS OF CANCER - Heat Shock Proteins a a Hypothesis Strongest inducable heat shock proteins (HSP27 and HSP70) are a also involved in the pathogenesis of TETs a a HALLMARKS OF CANCER F. Colotta et al. 2007

14 Methods LOCAL FUNCTION - Immunhistochemistry: HSP27 and HSP70 Thymic Specimens 101 TETs 24 non-malignant specimens Staining intensity: 0-3 SYSTEMIC FUNCTION ELISA HSP27 and HSP70 Serum samples 46 patients with TETs 16 patients pre and post OP 33 patients with TH 49 volunteers

15 Results Part 1- IMMUNOHISTOCHEMISTRY

16 Results I HSP expression and clinical characteristics HSP expression in TETs Clinicopathological Cyto HSP27 Cyto HSP70 Nucl HSP70 characteristics Nr. Mean±SD Nr. Mean±SD Nr. Mean±SD WHO A ± ± ±0.9 AB ± ± ±0.7 B ± ± ±1.1 B ± ± ±0.7 B ± ± ±0.7 TC ± ± ±1.1 MNT 4 3.0± ± ±0.6 TNET 3 0.5± ± ±0.6 p-value <0.001 a a a Masaoka-Koga Stage I ± ± ±0.6 II ± ± ±0.9 III ± ± ±1.0 IV ± ± ±1.2 p-value a a a

17 Results II HSP27 in TETs One way ANOVA: p<0.001 A B3 TC TNET

18 Results III HSP70 in TETs One way ANOVA: p=0.003 AB B3 TC TNET

19 Results IV Impact of HSP expression on outcome Kaplan-Meier Analysis

20 Results V Univariable Analysis (Cox-Regression Analysis) Freedom from Recurrence Cytoplasmic HSP27 Nuclear HSP70 weak moderate strong weak moderate strong months HR 5.594; 95% CI [ ]; p=0.034 months HR 3.990; 95% CI [ ]; p=0.025

21 HSP70 HSP27 Results VI HSP expression in non-malignant thymic specimens Fetal FTH mtec ctec

22 Fetal thymus Adult thymus Results VII Doublestaining HSP70 / Lu-5 and HSP70 / CD68(PGM1) in physiologic thymic specimens HSP70 brown Lu5 red HSP70 brown CD68 red HSP70 brown Lu5 red HSP70 brown CD68 red

23 Results Part 2- ELISA

24 Results HSP27 and HSP70 serum levels in patients with TETs

25 HSP serum concentrations decrease after surgical tumor resection Pre OP one day before operation Post OP at least one month after operation and/or adjuvant therapy No sign of recurrence Mean follow up: months

26 Results HSP27 and HSP70 serum levels according to tumor stage HSP expression in TETs Clinicopathological Cyto HSP27 Cyto HSP70 Nucl HSP70 characteristics Nr. Mean±SD Nr. Mean±SD Nr. Mean±SD Masaoka-Koga Stage I ± ± ±0.6 II ± ± ±0.9 III ± ± ±1.0 IV ± ± ±1.2 p-value a a a

27 HSP serum concentrations in patients with MG

28 Summary IMMUNOHISTOCHEMISTRY HSP27 and 70 were generally expressed in TETs (target for treatment) HSP are generally expressed on thymic epithelial cells (TECs) Weak HSP expression represented a worse prognostic factor for FFR and was associated with worse freedom from recurrence (prognosis) Stronger expression of HSP in TCs and thymomas than TNET (origin of ELISA tumor and oncologic behaviour) Serum HSP expression was elevated in TETs and advanced tumor stages (chronic inflammation and tumor microenvironment) Tumor resection -> significantly decrease of HSP serum concentrations (oncologic follow up) Elevated levels of HSPs in myasthenia gravis (Pathogenesis of MG)

29 Conclusion and Outlook From Bench to Bedside 1. Targeted Therapy: HSPs expressed in the majority of TETs; in literature combination of HSP inhibitors and ChT -> better response and survival

30 Conclusion and Outlook From Bench to Bedside 1. Targeted Therapy: HSPs expressed in the majority of TETs; in literature combination of HSP inhibitors and ChT -> better response and survival 2. Biomarker Extracellular HSP has been linked to chronic inflammation HSP serum levels decrease after tumor resection -> might be helpful for oncologic follow up to detect tumor recurrence Proinflammatory markers might be also helpful for oncologic follow up: CRP, Fibrinogen, NLR,...

31 Acknowledgement s Christian Doppler Laboratory for Cardiac and Thoracic Diagnosis and Regeneration Hendrik Jan Ankersmit Bernhard Moser Christine Bekos Philipp Hacker Thomas Raunegger Andreas Mitterbauer Jonathan Kliman Thomas Haider Clinical Institute of Pathology Ana-Iris Schiefer Leonhard Müllauer Department of Thoracic Surgery Bernhard Moser Walter Klepetko Department of Cardiology Mariann Gyöngyösi Thank you for your attention!