4. Ki-67 IHC to distinguish typical and
atypical carcinoid
H&E
Ki-61
typical carcinoid atypical carcinoid
Rekhtman, Arch Pathol Lab Med 2010
5. Arrray comparative genomic
hypridization-based characterization of
pulmonary neuroendocrine tumors
Voortman, PNAS 2010
High degree CNAs in SCLC but
not in bronchial carinoids
Common CNAs in
neuroendocrine
tumors
6. Clinical presentation of pulmonary
carcinoids
Symptoms:
One third incidental finding
Cough, recurrent pneumonia, and hemoptysis
Carcinoid syndrome exceedingly rare
Location:
Central > peripheral
Nodal involvement:
Associated with atypical
carcinoid
Detterbeck, Ann Thorac Surg 2010
9. Mesothelioma in Europe
Peak incidence
around 2020
British mesothelioma
register and male death
rates for cancer
of the pleura from
6 European countries
Statistical modeling taking
into account asbestos
legislation and the long
latency period
Peto, BJC 1999
Peak leveling off between 2010 and 2015
Perlucchi, BJC 2004; Hodgson BJC 2005
10. Latency period in pleural mesothelioma
after asbestos-exposure
Data collected by the Italian mesothelioma registry in the
period 1993-2000: median latency 44.6 years
Marinaccio, EJC 2007
12. Alterations of NF2 and LATS
Mutations in NF2 have been described in 40% of
mesothelioma
Bianchi, PNAS 1995; Sekido, CR 1995; Deguen, IJC 1998
In tumors without NF2 truncation, NF2 activity is
inhibited by phosphorylation, for example by
increased expression of CPI-17
Thurneysen, Lung Cancer 2009
Loss of NF2 (merlin) correlates with activation of
PI3K/mTORC1 signalling and sensitivity to
rapamycin
Lopez-Lago, MCB 2009
LATS (large tumor suppressor homolog 2) is a
tumor supressor gene in mesothelioma
Murakami, Mol Cell Pathol; 2011
13. NF2 is a „gatekeeper“ during tissue
repair
Sonic hedgehog signaling
NF2
Mst
WW45
Mob
Lats
YAP
YAP
YAP
X survivin
amphiregulin
Ser127P
P
P
NF2
Mst
WW45
Mob
Lats
YAP
YAP
X
survivin
amphiregulin
P
P
Stimulation of repair in
NF2-deficientcancer cells
Sonic hedgehog signaling
NF2
Normal tissue repair
Hippo
pathway
14. Soluble mesothelin-related peptide
• Mesothelin is a cell surface glycoprotein, expressed
on normal mesothelial cells and > 90% of
mesotheliomas (binds to CA125)
• Soluble mesothelin-related proteins in serum
• Target for antibody therapy
Robinson,
Lancet 2003
Cristaudo,
Clin Cancer Res 2007
Pass, ATS 2008
15. Systemic therapy
Chemotherapy provides symptom relief
Based on a landmark study of Vogelzang et al.,
the combination of cisplatin and pemetrexed has
become the preferred chemotherapy regimen
Most current studies examining neoadjuvant
chemotherapy followed by extrapleural
pneumonectomy include combined cisplatin and
pemetrexed chemotherapy
Optimal second line chemotherapy is not defined,
vinorelbine might be a good choice
Novel and targeting agents: so far no or very limited
success
16. Pemetrexed + Cisplatin vs Cisplatin:
Tumor Response Rates and Survival
Vogelzang , JCO 2003
17. Surgery and multimodality therapy
The role of surgery continues to be a matter of debate
– Radical resectability?
– Extrapleural pneumonectomy or pleurectomy and
decortication?
– Impact on survival?
– Lack of prospective randomized data
However:
– Longest median survival and long term survivors
reported in series with multimodality therapy
including EPP
– Surgical mortality in experienced centers dropped
to around 3%
18. Multimodality therapy including
extrapleural pneumonectomy (EPP)
Boston: EPP with adjuvant chemotherapy and
radiotherapy:
Retrospective series on 176/183 pts surviving EPP
MST 19 months, periop. mortality 3.8%, 35% local failure
Sugarbaker JTCVS 1999; Baldini, ATS 1997
Zürich/SAKK: Neoadjuvant chemotherapy and EPP
(± radiotherapy):
Prospective phase II study on 61 pts
MST by intent to treat 19.8 months, operative mortality 2%
EPP 45 pts (74%), MST 23.8 months
Weder and Stahel, Ann Oncol 2007
20. Well-differentiated papillary
mesothelioma of the pleura
24 cases
Equal proportion of man
and women, mean age 60
years, less than half h h/o
asbestos exposure
Dysnpnea and recurrent
pleural effusion
Thorocoscopy demonstread multipe millimeter
nodues on the parieal and or visceral pleura
2/6 with no treatment survived 73 and 83 months
17 pts alive with disease, including 11 longer than 2
years and 2 with a f/u of 5 and 10 years
Galateau-Sallé, J Surg Pathol 2004
21. Classification of Thymic Tumors
Thymic tumors are epithelial tumors,
often admixed with lymphocytes
(mostly T-cells)
Incidence: 1-5/million/year
Morphology: very heterogeneous
– „American“ Classification
– Marino/Müller-Hermelink Classifikation
– WHO-Classification (1999)
22. WHO-EinteilungWHO-Einteilung
WHO types
A = medullary, B = cortical, C = carcinoma
WHO-Classifikation of Thymic Tumors
A: « atrophic », the thymic cells of
adult life
B: « bioactive » biologically active
organ of the fetus / infant
C: « carcinoma »
23. WHO types: Morphology and behaviour
A = medullary, B = cortical, C = carcinoma
A Medullary thymoma
AB Mixed thymoma
B1 Predominant cortical thymoma
B2 Cortical thymoma
B3 Well-differentiated thymic ca.
C Thymic carcinoma
Mostly en-
capsulated
WHO-EinteilungWHO-Einteilung
Mostly
invasive
Often
metastatic
WHO-Classifikation of Thymic Tumors
24. WHO type C: No longer suggested, but replaced
by descriptive terms
Squamous cell carcinoma (most common)
Basaloid carcinoma
Mucoepidermoid carcinoma
Lymphoepithelioma-like carcinoma
Sarcomatoid carcinoma
Clear cell carcinoma
Papillary adenocarcinoma
Non-palliary adenocarcinoma
Undifferentiated carcinoma of the thymus
Thymic neuroendocrine tumors
WHO-EinteilungWHO-EinteilungWHO-Classification of Thymic Tumors
27. Heterogeneous disease, in particular
thymoma vs thymic carcinoma
No randomized studies
Very little prospective studies, mostly single
center experience (retrospective analysis)
Many review articles, recent reviews include:
Treatment recommendatons
28. Tomaszek,
Ann Thorac Surg
2009
(Mayo Clinic)
Girard,
JTO 2009
(European)
Falkson,
JTO 2009
(Cancer Care Ontario)
Treatment recommendations
29. Stage I: Surgery
Stage II: Surgery, postoperative radiotherapy
recommended after incomplete resection
Stage III/IVA: Multimodality therapy, mostly
neoadjuvant chemotherapy followed by
surgery with our without radiotherapy
Stage IVB: Chemotherapy
Treatment recommendations
31. Recommendation on postoperative
radiotherapy for stage II
European:
– Incomplete resection
– Radiation dose 60-65 Gy in case of incomplete resection
– Otherwise controversial
Ontario:
– Routine XRT not recommended
– Restricted to “high risk”: Capsular invasion, close
margins, WHO type B, adherence to pericardium
Mayo:
– Controversial for completely resected tumors
– Consider for WHO B2, B3 or C
– Increase in dose or extension in field does not improve
outcome
32. Reommendation on potentially
resectable disease
European:
– Surgery and postoperative radiotherapy
Ontario:
– Evaluation for multimodality therapy
– Neoadjuvant chemo(radio)therapy and surgery,
considering volume
Mayo:
– Multimodality therapy
33. Neoadjuvant Chemotherapy, Surgery,
and Radiotherapy in Advanced Thymoma
Publication Regimen Pts RR
(%)
Complete
resection
Survival
Berrutti, BJC 1999 PAC 16 81% 56% 25% 5-y
Kim, Lung Cancer
2007
PAC 22 77% 73% 79% 7-y
Lucchi, JTO 2006 PEA 30 73% 77% 82% 10-y
Yokio, JTO 2007 CAMP 17 92% 18% 81% 10-y
Yokio, JTO 2007 CAMP 17 92% 18% 81% 10-y
Lemma, ASCO 2008 CP 23 35% ? ~ 80? 5-y
Wright, Ann Thorac
Surg 2008
PE 10 40% 80% 69% 5-yIm
portance
of surgery
for survival!
34. Basis for treatment decision for the individual patient:
Evidence-based guidelines: N/A
Prospective randomized studies: N/A
Few prospective phase II studies, mostly
retrospective single center experience:
– RR ≈ 70% with cyclophosphamide, doxorubicine
and cisplatin combinations
– RR ≈ 40% with etoposide and cisplatin
combinations
Review articles
Chemotherapy of Thymic Tumors
36. 36 | The future development of systemic therapy of non-
small cell lung cancer will be based on molecular
tumor characteristics
Advanced adenocarcinoma:
Evolving molecular
determinants
Pao & Girard,
Lancet Oncol,
2011
ETOP | Zürich, March 17, 2011
37. 37 | Translational research in lung cancer: The advances
over the last years
Advanced adenocarcinoma:
Molecular targets
•EGFR mutation
First line TKIs
•ALK fusion gene product
ETOP | Zürich, March 17, 2011
38. 38 | Translational research in lung cancer: Evolving
targets
Advanced adenocarcinoma: Evolving targets
•EGFR mutation: Overcoming
TKI resistance
•MET amplification
•Targeting HER mutations
•Targeting BRAF mutations
ETOP | Zürich, March 17, 2011
39. 39 | Translational research in lung cancer: Evolving
targets
Advanced squamous cell carcinoma: Evolving targets
• FGFR1 amplification
Independent of histology
•EGFR IHC revisited
ETOP | Zürich, March 17, 2011
Weiss, Sci
Transl Med 2010
40. LUNGSCAPE is a translational research
project designed by ETOP
(www.lungscape.org)
Lugano, January 30, 2015
41. Austria
• CECOG – Central European
Cooperative Oncology Group
Belgium
• ELCWP – European Lung Cancer
Working Party
• EORTC Lung Cancer
• Leuven Lung Cancer Group
• TOGA – Thoracale Oncologie
Groep Antwerpen
Czech Republic
• Czech Lung Cancer
Cooperative Group
Denmark
• DLCG – Danish Lung Cancer Group
• DOLG – Danish Oncological
Lungcancer Group
France
• GFPC – Groupe Français de
Pneumo-Cancérologie
• IFCT – Intergroupe francophone de
Cancérologie thoracique
• IGR – Institut Gustave Roussy
Germany
• AOT – Arbeitsgemeinschaft
Onkologische Thoraxchirurgie
• Arbeitsgruppe Thorakale Onkologie
der Arbeitsgemeinschaft Internistische
Onkologie der Deutschen
Krebsgesellschaft
• Lung Cancer Group Cologne
Greece
• HeCOG – Hellenic Co-operative
Oncology Group
• HORG – Hellenic Oncology
Research Group
Hungary
• Thoracic Oncology Program
Italy
• AIOT – Associazione Italiana di
Oncologia Toracica
Poland
• Polish Lung Cancer Group
• Medical University of Gdansk
TOP Group
Portugal
• GECP – Grupo de estudos do
cancro do pulmão
Spain
• SLCG – Spanish Lung
Cancer Group
Sweden
• Swedish Lung Cancer
Study Group
Switzerland
• SAKK – Schweizerische
Arbeitsgemeinschaft fuer Klinische
Krebsforschung
The Netherlands
• NVALT – Nederlandse Vereniging
van Artsen voor Longziekten en
Tuberculose
• ROTS – Rotterdam Thoracic
Oncology Study Group
United Kingdom/Ireland
• Birmingham Group
• BTOG – British Thoracic Oncology Group
• London Lung Cancer Group
• Manchester Lung Cancer Group
• National Cancer Research Institute –
Lung Cancer Clinical Study Group
Participating groups
and institutions
42. 42 | Molecular based clinical trials in lung cancer: Issues
Molecular pathology both at diagnosis and at relapse for
definition or stratification of study population mandatory
• Centralized analysis or standardization of methodologies
between sites
• Availability of integrated services at sites
Rarity of molecular subgroups
• Large networks of sites necessary to detect eligible patients
• Optimal number or sites for a given trial
Emphasis on early decision in molecularly-driven trials
• New models of collaboration with diagnostic and
pharmaceutical companies
ETOP | LUNGSCAPE | Malta, April 10, 2011
43. About LUNGSCAPE
• The LUNGSCAPE addresses the challenges of studying the
molecular epidemiology of lung cancer
• by coordinating and harmonizing the procedures of of lung
cancer specialists in translational research across Europe
• by facilitating analysis of larger series of cases.
• Specifically, LUNGSCAPE will:
• Establish a virtual NSCLC bank with (anonymized) patient
specific information including molecular pathology as
resource for research and hypotheses generation for future
diagnostic platforms and biomarker driven clinical trials
• Samples will be analyzed at the sites of origin according to
SOPs
• Web-based electronic data base (lungscape.org)
43 |
ETOP | LUNGSCAPE | Zürich, March 17, 2011
44. Web-based data bank: Comprehensive clinical data
capture
44 |
ETOP | LUNGSCAPE | Malta, April 10, 2011
45. 45 | Stepwise evolution
• Step 1:
Retrospective analysis of 1500 completely resected NSCLC
from a limited number sites:
Mutation testing, immunohistochemistry, selected FISH on
formalin-fixed, paraffin-embedded tumor tissue
• Step 2:
Expansion to biopsies from advanced disease and a phased
approach increasing to the number of participating sites with
the aim to have participation from at least one site from all
countries represented in ETOP
• Further steps and issues under considerations:
Enlargement of biobank, exon sequencing (selected frozen
tissue), circulating biomarkers, technology platforms, resource
utilization and health economics research
ETOP | LUNGSCAPE | EMCTO | Lugano, February 24, 2011
46. Thank you for listening!
ETOP | European Thoracic Oncology Platform | c/o IBCSG | Effingerstrasse 40 | 3008 Bern | www.etop.ch
Visit us at www.etop.ch
Hinweis der Redaktion
Thymome und Thymuskarzinome sind epitheliale Tumoren, die von dem feinen Netzwerk an epithelialen Zellen des Thymus ausgehen. Dies ist eine immunhistochemische Färbung für Zytokeratin, die das Netzwerk von epithelialen Zellen des Thymus darstellt.
In der Vergangenheit hat es zwei Klassifikationen von Thymomen gegeben, die seit 1999 durch die WHO Klassifikation der Thymome ersetzt ist.
A ersetzt das wort medullär, b das wort Kortikal und C das Karzinom im offensichtlich malignen Thymuskarzinom