64
HERMES SUMMER SCHOOL
Session 6 – Thoracic Tumours I
NSCLC/SCLC – Diagnosis and staging of
thoracic tumours
Rudolf M. Huber
University of Munich
Thoracic Oncology Centre Munich
Conflict of interest disclosure I have the following, real or perceived direct or indirect conflicts of interest that
relate to this presentation:
Affiliation / financial interest Nature of conflict / commercial company name
Grants/research support (to myself, myinstitution or department):
Funding by German Ministry of Education and Research (BMBF), German Research Society (DFG), Wilhelm-Sander-Stiftung
Advisory boards, presentations: Ariad, AstraZeneca, Boehringer Ingelheim, BMS, Clovis, Lilly, Novartis, Roche
Other support or other potentialconflict of interest:
Clinical trials with Amgen, Ariad, AstraZeneca, Boehringer Ingelheim, BMS, Clovis, DaichiSankyio, MSD, Novartis, Pfizer, Pierre Fabre, Roche
Introduction
AIMS
• To provide knowledge about
epidemiology, mortality, risk factors
and prognostic factors
• To describe the staging procedure
• To outline the diagnostic strategies
THORACIC ONCOLOGY
Lung cancer
Adenoid-cystic Ca, carcinoid
Endobronchial and pulmonary metastases
Benign tumours (hamartoma, infection etc.)
Tumours of the pleura
Mediastinal tumours
5-YEAR SURVIVAL
OF TUMOUR
PATIENTS
EUROCARE-4Lancet Oncol 2007:8:773
Lung n = 343473, 5-Y-S 12.6 %
All n = 2699086, 5-Y-S 51.9 %
Pleura n = 11851, 5-Y-S 7.5 %
LUNG CANCER
• non small cell lung cancer 80 %
• small cell lung cancer
– USA 13 – 20 %
– Germany 20 %
50–55%* 35–40%† 10%*
Adeno-Ca Squamous cell Ca Large cell Ca
*Image from www.surgical-pathology.com; †Image from http://www.lmp.ualberta.ca/resources/pathoimages/PC-S.htm
b6560
Lung cancer 386 300, 12,1%2004 258 000
Incidence MortalityLung cancer 334 800, 19,7%2004 234 000
Ferlay J ea. Ann Oncol 2007 18:581-592; doi:10.1093/annonc/mdl498
In Germany 42319 patients died 2008 due to lung cancer
CANCER INCIDENCE AND MORTALITY IN EUROPE
2006 (NUMBER X 1000)
FIVE-YEAR SURVIVAL RATES: 1975-2004
USA
American Cancer Society: Cancer Facts and Figures 2009
0
5
10
15
20
25
30
35
40
45
Stage I Stage II Stage III Stage IV
NSCLC STAGING AT PRESENTATION
Mountain CF, Semin Surg Oncol. 2000
SCLC STAGING AT PRESENTATION
• small cell lung cancer
– Stage IV 80 %
– Stage I – IIIB 20 %
T = Primary tumour
N = involvement of regional lymph nodes
M = distant metastasis
Lungcancer
STAGING
TNM-Classification
• TNM: description of anatomical extent of the disease
Detterbeck FC ea. Chest 2009;136:260-271
STAGES 0, I, AND II – TNM 7 SINCE 2010
T – RECOMMENDATIONS ADDITIONAL
NODULES – TNM 7
Reclassify T4 tumours with
additional nodules in the
primary lobe as T3
Reclassify M1 with additional
nodules in a different
ipsilateral lobe as T4
Detterbeck FC ea. Chest 2009;136:260-271
STAGES IIIA AND IIIB – TNM 7 SINCE 2010
T – RECOMMENDATIONS PLEURAL
DISSEMINATION – TNM 7
Reclassify T4 tumours with pleural
dissemination as M1
OVERALL SURVIVAL CURVES FOR
PROPOSED BEST STAGES (IASLC DATA)
Detterbeck FC ea. Chest 2009;136:260-271
STAGE IV – TNM 7 SINCE 2010
TYPES OF STAGING ASSESSMENTS
Prefix Name Definition
c Clinical
Prior to initiation of any
treatment, using any and all
information available (eg,
including mediastinoscopy)
p PathologicAfter resection, based on
pathologic assessment
y RestagingAfter part or all of the treatment
has been given
r Recurrence Stage at time of a recurrence
a Autopsy Stage as determined by autopsy
Detterbeck FC ea. Chest 2009;136:260-271
RESIDUAL TUMOR AFTER
TREATMENT
Symbol Name Definition
R0 No residualNo identifiable tumor remaining; negative surgical margins
R1Microscopic residual
Microscopically positive margins but no visible tumor remaining
R2Gross residual
Gross (visible or palpab-le) tumour remaining
Detterbeck FC ea. Chest 2009;136:260-271
STAGE ATTRIBUTION SINCE 2010 (TNM 7)
N0 N1 N2 N3 M1a+b
T1a+b0-2-3cm
IA IIA IIIA IIIB IV
T2a3-5cm
IB IIA IIIA IIIB IV
T2b5-7cm
IIA IIB IIIA IIIB IV
T3 IIB IIIA IIIA IIIB IV
T4 IIIA IIIA IIIB IIIB IV
M1a+b IV IV IV IV IV
HuberAmsterdam, 26. 9. 2011
André F ea. JCO 18 (2000)
PROBLEM MEDIASTINUM: RESECTED N2
NSCLC
N2 Subgroups and survival
STAGE IIIA (N 2) – SUBSETS
• III A (1)incidental nodal metastases found on final surgical pathology
• III A (2)single nodal metastasis, recognized intraoperatively
• III A (3)Mediastinal nodal metastases, detected preoperatively by mediastinoscopy or PET
• III A (4)„Bulky“, multi-station, inoperable
ACCP Guideline. Chest 2003
ACCURACY OF STAGING
NSCLC – N2 DISEASE
Weder W. Ann Oncol 19 (Supplement 7): vii28–vii30, 2008
TechniqueSensiti-vity %
Specificity %
NPV %
PPV %
CT 57 82 83 56
PET 84 89 93 79
Blind TBNA 76 96 71 100
EUS-FNA 88 91 77 98
Mediastinoscopy 81 100 91 100
Detterbeck FC ea. Chest 2009;136:260-271
STAGE GROUPING
Clinical
Pathological
subclassify
T1 into T1a (≤1 cm),
T1b (>1 to ≤2 cm),
T1c (>2 to ≤3 cm);
subclassify
T2 into T2a (>3 to ≤4 cm)
T2b (>4 to ≤5 cm)
reclassify tumors greater than 5 to less than or
equal to 7 cm as T3
reclassify tumors greater than 7 cm as T4
group involvement of main bronchus as T2
regardless of distance from carina
group partial and total atelectasis/pneumonitis as T2
reclassify diaphragm invasion as T4
delete mediastinal pleura invasion as a T descriptor.
RECOMMENDED CHANGES FOR THE T-
DESCRIPTORS (FOR TNM 8)
Current N descriptors adequately predict the prognosis and
therefore should be maintained in the forthcoming staging
system
Recommendation
physicians record the number of metastatic
lymph nodes (or stations)
further classify the N category using new descriptors
N1a (single)
N1b (multiple)
N2a1 (single without N1 - skip)
N2a2 (single with N1)
N2b (multiple)
N3
for further testing
RECOMMENDED CHANGES FOR THE N-
DESCRIPTORS (FOR TNM 8)
In this revision of the staging system
Continued to be grouped as M1a categorypleural/pericardial effusions
contralateral/bilateral lung nodules
contralateral/bilateral pleural nodules
or a combination of multiple of these parameters
Newly designated to the M1b categorySingle metastatic lesions in a single distant organ
Reclassified as M1c categoryMultiple lesions in a single organ
Multiple lesions in multiple organs
This new division can serve as a first step into providing
rational definitions for an oligometastatic disease stage in non–
small cell lung cancer in the future
RECOMMENDED CHANGES FOR THE M-
DESCRIPTORS (FOR TNM 8)
NSCLC - PROGNOSIS
0
10
20
30
40
50
60
70
80
90
100
5-year-survival
I A
(%)
I B II A II B II B III A III A III B III B IV
A third of pts with newly diagnosed NSCLC have locally advanced disease not amenable to curative resection
Lung Cancer Prognosis – Histology (N=2,155)
Clinical measure of disease extent
Squamous cell (n=996)
Adeno-carcinoma (n=521)
Undifferen-tiated large cell (n=195)
Undifferen-tiated small cell (n=368)
Relative Percentage Surviving 5 Years
Lymph node negative
30 18 20 < 3
No metastases
30 19 17 2
Distal metastases
< 1 < 1 0 0
Mod. from Mountain C ea. Am. J. Roentgenol., Jan 1974; 120: 130 - 138
IASLC/ATS/ERS CLASSIFICATION –
SUBTYPING OF ADENOCARCINOMA
• Bad prognosis
Solid, micropapillary
• Moderate prognosis
Papillary, acinar
• Good prognosis
Lepidic (non-mucinous)
1. Analysis of all
differentiation patterns
in 5% steps
2. Definition of the
predominant
differentiation pattern
Travis WD ea. J Thorac Oncol 2011; 6: 244 – 285
STAGE I ADENOCARCINOMA
(N=514) RECURRENCE-FREE SURVIVAL (RFS) BY IASLC
HISTOLOGIC TYPE
Yoshizawa, Modern Pathology (2011)
P=0.003
Micropapillary &
Solid Predominant
Colloid, Mucinous Ad
AIS, MIA
Lepidic, Papillary & Acinar
Predominant
Histologic Type
(N)
5 Year
RFS
%
AIS (1) 100
MIA (8) 100
Lepidic NM (29) 90
Papillary (143) 83
Acinar (232) 85
Mucinous
Adenoca (13)
76
Solid (67) 71
Micropapillary
(12)
64
Colloid (9) 71
IASLC/ATS/ERS
classification in small
samples
Travis WD ea. J Thorac Oncol
2011; 6: 244 – 285
Travis WD ea. (2011) J Thorac Oncol, 6(2): 244-285
Travis WD ea. (2011) J ThoracOncol, 6(2): 244-285
TISSUE APPROACH
• Central lesion: bronchoscopy including
various methods of tissue sampling
• Peripheral lesion ≥ 2 cm transthoracic needle
aspiration (TTNA) or bronchoscopy under
radiological guidance
• Peripheral lesions < 2 cm TTNA or
bronchoscopy using modern navigation
methods such as radial probe ultrasound or
electromagnetic techniques
German Respiratory Society (DGP). Pneumologie 2010; 64, Supp.2: e1– e1
LUNG CANCER IN NEVER SMOKERS
• < 100 cigarettes overall
Histology
– Adenocarcinoma 60.8%,
– NSCLC not otherwise specified 14.4%
– bronchiolo-alveolar carcinoma 13.6%
– squamous cell carcinoma 8.8%
– large cell type 2.4%
Govindan R ea. JTO
Rudin CM ea. Clin Cancer Res 2009;15:5622-5625
CANCER DEATH RATES IN USA, 2008
Rudin C M et al. Clin Cancer Res 2009;15:5646-5661
TP53 MUTATION SPECTRA IN CANCERS
IN LUNG CANCER BY SMOKING STATUS
Large amount of genetic changes, “inflamed” tumour type
MUTATIONS EXON 19 AND 21 – SMOKING
Pham D ea. JCO 24 (2006): 1700 - 1704
BIOLOGICAL TARGETS
Hanahan D, Weinberg RA. Cell 144 (2011)b6324
Huber
Shaw AT ea. N Engl J Med 2011;365:158-167
GENETIC ABNORMALITIES IN ADENOCARCINOMAS
OF THE LUNG (SINGLE DRIVER MUTATIONS)
GENOMIC ALTERATIONS IN SQUAMOUS-CELL LUNG
CANCER
P Hammerman introduction to the Plenary Presidential Symposium, WCLC 2011
Gene Event type Frequency
FGFR1 Amplification 20–25%
FGFR2 Mutation 5%
PIK3CA Mutation 9%
PTEN Mutation/Deletion 18%
CCND1 Amplification 8%
CDKN2A Deletion/Mutation 45%
PDGFRA Amplification/Mutation 9%
EGFR Amplification 10%
MCL1 Amplification 10%
BRAF Mutation 3%
DDR2 Mutation 4%
ERBB2 Amplification 2%
Performance Status
Also relevant:
- Weight loss
- In part LDH ...
- Biology
PROGNOSTIC FACTORS
IN LUNG CANCER
LUNG CANCER – RISK FACTORS
• Smoking• Radon
• Asbestos (Nr. 4104 BeKV), ionising radiation (Nr. 2402 BeKV), ...
• 10 – 15 % of patients are NON smokers
• Hereditary (OR 2.4 – 5.3, smoking hyperadditive)
LUNG CANCER – DIAGNOSTIC APPROACH
Chest X-ray
CT thorax and upper abdomen
PET-CT
Bronchoscopy, EBUS
Thoracoscopy
Mediastinoscopy
Transthoracic needle aspiration
Functional evaluation
Staging
Histology –treatment options
Huber
SCLC – VENA CAVA SUPERIOR SYNDROME
HuberWS 2009
ONE-
SIDED
HYPER-
LUCENT
LUNG
WA, male, * 8. 2. 1927
"STATUS ASTHMATICUS"
EARLY LUNG CANCER ACTION PROJECT IN NEW YORK HENSCHKE C EA. LANCET 354 (1999)
4 in right and left mainstem bronchus, mediastinum were excluded
The National Lung Screening Trial Research Team. N Engl J Med 2011. DOI: 10.1056/NEJMoa1102873
NLST: CUMULATIVE NUMBERS OF LUNG CANCERS AND OF DEATHS FROM LUNG
CANCER
Relative reduction in mortality from lung cancer with low-dose CT screening of 20.0% (95% CI, 6.8 to 26.7; P = 0.004).
White light PPIX - fluroescence
FLUORESCENCE - BRONCHOSCOPY
Invasive squamous cell lung cancer right main stem bronchus
Infections
Gastro-
enterology
Hematology
Nephrology
CrCl
ultrasound
PneumologyAge
Gender
BMI
Neurology
CNS
PNP
Cardio-
vascular
FUNCTIONAL TREATABILITY
Smoking and age cause damages to many organs
ERS/ESTS. Eur Respir J 2009;34 782
CARDIOVASCULAR SITUATION
ERS/ESTS. Eur Respir J 2009;34 782
LUNG FUNCTION
INDIVIDUALISED MANAGEMENT?
Country of Origin of All Patients with Thoracic Malignancies October -
December 2009
3%
6%
14%
67%
2%2%
2%2%
2%
Ethiopia
Mongolia
Spain
USA
Ukraine
Italy
Croatia
Turkey
Germany
Tufman et al., ERS 2011
INDIVIDUALISED THERAPYParticipation in a patient advocacy group in lung cancer
95%
5%
keine Teilnahme
aktive Teilnahme
Own unpublished data
Non-participantsParticipants
Younger age
75 % female
50 % never smokers, 50 % ex smokers
adenocarcinoma
25 % EGFR mutation
YOU JUST CAN’T CALL IT LUNG CANCER
ANYMORE
• Rather than prescribing treatment for a
patient with “stage IV NSCLC,” clinicians
should move toward describing the
same patient as T2N2M1a, stage IV,
invasive mucinous adenocarcinoma,
epidermal growth factor receptor +, and
Kras -.
• You just cannot call it lung cancer
anymoreSimon GR, Silvestri GA. JTO 6 (2011),239 - 240
YOU JUST CAN’T CALL IT LUNG CANCER
ANYMORE
• Functional evaluation
• Geriatric assessment
• …
Simon GR, Silvestri GA. JTO 6 (2011),239 - 240
Conclusion
• Lung cancer is a common disease with a
poor prognosis
• Prognosis is determined by– extent of the disease
– exact histology and driver genetic alterations
– performance status
– functional situation and further conditions of
the patient
• A thorough evaluation of the patient and
the tumour is relevant for the
management of the disease
