Lung cancer

Gabriela Jimborean
UMF Tg. Mures
Pulmonology Clinic
 Lung cancer great morbidity and
mortality
WHO

From 1985 LC is the leading cause of CC morbidity and death around the world
First place in all CC in men
Third place in women (after breast, uterine)
2005
> 12 million people diagnosed with LC
2020
The incidence may increase to 15 million
2030
Explosion - new cases - 27 million
 Epidemiology - mortality
WHO
2005> 7.6 mill deaths / year
(70% in low-income countries)
2005 - 2015 - 85 mill deaths
(including not treated cases) [1,2]

M - 40% ooo men, M - 8.5%ooo in women

2030 - 17 mill / year

1.Siegel R, Ward E, Brawley O, et al. Cancer statistics, 2011: the impact of eliminating socioeconomic and racial
disparities on premature cancer deaths. CA Cancer J Clin. 2011;61(4):212236
2. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin. 2011;61(2):6990
CA Cancer J Clin. 2011 Mar-Apr;61(2):69-90. doi: 10.3322/caac.20107. Epub 2011 Feb 4.
 LC extraordinary severity
At the time of diagnosis only 20-25% are operable/curable
50% of patients aged 45 to 65 (very active people)
NO screening in Romania, low level world wide, only in USA - !!! Screening
decrease mortality with 20% !!!
Without treatment, most of cases die within the first year after diagnosis
7 of 8 j are asymptomatic long time, establishing the diagnosis in advanced
stages of invasive complications

5 years suvival - 15% pt. all forms including treated (except "solitary pulmonary
nodule" > 80% - st. IA - T1 N0 M0)
Age gets younger
% of women is growing F: B ----1: 5 ( women empowerment)
Multiple risk factors are avoidable

Lung Cancer Screening With Low-Dose Computed Tomography: Costs, National Expenditures, and Cost-Effectiveness, Journal of the National Comprehensive Cancer Network: JNCCN
10(2):267-75
 Risk factors for LC
Active and passive smoking
85-90% of LC are smokers
11% of smokers - LC ( 13 x increase risk for LC)
The risk of 10-30 x higher compared to NS
The risk correlates with:
No of cigarettes during life = Year PACKS
Type cigarettes, filter, deep of inhalation
The age at starting smoking
Genetic risk
Exposure
Chronic diseases
risk LC is very slow it decreases in
15 y after smoking cessation
but does not touch the low risk of
non-smokers
 Adenocarcinoma risk factors
1. ADC in smokers including passive (the most significant
identified risk factor)
2. ADC in nonsmokers
more common in women than in men
more likely in younger people than other types of LC
non-smoking-associated LC is considered a distinct
disease entity, where specific molecular and genetic
tumor characteristics are being recognized

3. Exposure to Az, Cr, Radon, Ni, gases, HC

4. Genetic factors Cr.15 (risk 15 30%)
5. Chronic respiratory diseases - chronic inflammation
- Bronchiectasis
- Old TB scars, Silicosis
- Pulmonary fibrosis
- COPD

Diets high in fruits and vegetables seem to decrease risk

Global cancer statistics.Jemal A1, Bray F, Center MM, Ferlay J, Ward E, Forman D.
Brenda K. Edwards , Martin L. Brown , Phyllis A. Wingo , Holly L. Howe , Elizabeth Ward and all - Annual Report to the Nation on the Status of Cancer,
1975 2002, Featuring Population-Based Trends in Cancer Treatment Journal of the National Cancer Institute, Vol. 97, No. 19, October 5, 2005
Vineis P, Airoldi L, Veglia P, et al. Environmental tobacco smoke and risk of respiratory cancer and chronic obstructive pulmonary disease in former smokers and never smokers in the
EPIC prospective study. BMJ. 2005 Feb) 5;330(7486):277
 Histological types
of LC
Nonsmall cell lung cancer NSCLC 85%
Adenocarcinoma 35 - 40%
Squamous CC 40%
NSSLC probable squamos CC
NSCLC, probably adenocarcinoma
NSCLC - NOS
Carcinoid tumor
Large cell carcinoma 5 -10%
Other adenoid cistic, mucoepidermoid

Small cell carcinoma

 Clinical examination
Symptoms and signs: nonspecific, varied
LC is asymptomatic 1-2 years, 10% of LC - random discovery (Chest x ray)
Later symptoms are rapid progressive
Late diagnosis - 75% in advanced inoperable stages
Symptoms pulmonary, extrapulmonary (general nonmetastatic and
metastatic)
Very suggestive Risk factors
History of smoking
History of occupational exposure (carcinogens)
Old age
Hemoptysis
History of a prior neoplasia
The association of COPD and bronchial obstruction (spirometry)
Ping Yang, Mark S. Allen, Marie C. Aubry, Jason A. Wampfler, Randolph - Clinical Features of 5,628 Primary Lung Cancer Patients*Experience at Mayo Clinic
From 1997 to 2003, Chest 2005;128;452-462
R.P. Young, R.J. Hopkins, T. Christmas, P.N. Black, P. Metcalf, G.D. Gamble, COPD prevalence is increased in lung cancer, independent of age, sex and smoking
history, Eur Respir J 2009; 34: 380-386
 Symptoms and signs (1)
Central TU Peripheral TU
Cough very resistant to treatment Dry cough
with a changed character
Hemoptisis - bronhoscopy
Hemoptysis -! Bronchoscopy Dispneea
Pain - pleural invasion
Dyspnea, wheezing Recidivate Pneumonia - bronhoscopy
Post obstructive pneumonia (fever)
Repeated pneumonia - Bronchoscopy
Localized wheezing -! Bronchoscopy
Pain
Consolidation, pleural effusion,
atelectasis, localized sibilants

Asthenia, weight loss, loss of appetite,

pallor
Fever - may be the obstructive
pneumonia
Intrathoracic extension (2)
Locoregional tumor extension
T3 - chest wall, pleura, diaphragm,
phrenic nerve
T4 invasion of the mediastinum, heart,
recurrent N (dysphonia), great vessels (Sup
Vein Cave Vein Sy - edema, cyanosis),
trachea, carina, esophagus (dysphagia) (IIIB)
Lymph node extension N
N2, N3 (Inoperabile)
Extrathoracic nonmetastatic symptoms (3)
General symptoms - nonspecific
Peripheral/central neuropathies
Blood
Hyper coagulopathies
Anemia, polycythemia
Recurrent thrombophlebitis
Digital clubbing
Glomerulonephritis
Dermatomyositis, polymyositis
Endocrine sy
Hypercalcemia
Ectopic secretion of PTH, ADH
Hyper secretion of ACTH
 ADC great tendency to
dissemination (4)
Extrathoracic dissemination
CNS 47% - MRI, PET - CT
Bones 35% - Scintigraphy, PET - CT
Liver 22%
Adrenal glands 15% Abdominal US, CT, PET - CT
Thoracic dissemination
Pericardial efusion = M1a (TUS)
Malignant pleural extension with cytology - M1a (TUS)
Lymphatic obstruction - chilotorace - M1a (TUS)
Contralateral lung nodules M1a CT, PETCT
European Guidelines for Cancer NSCC: ESMO
Clinical Recommendations for diagnosis, treatment and follow-up 2015/2016
American guides NCCN guidelines - National Comprehensive Cancer Network Version
2017, NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines
2.2017 nccn.org

Correct Staging of LC + histopathological

evaluation + TU biomarker

= An essential component of ensuring the

quality in LC treatment
 Lung Cancer diagnosis algorithm
Suspected lung cancer
Symptoms
Peripheral tumor Risk factors
Bronchoscopy
Transcutaneous punction
US or CT guided + pleural Initial evaluation Central tumor/visible
liquid analysis Clinical Ex tumor
EBUS Chest x ray Bronchoscopy
Video thoracoscopy VATS Thoracic CT scan Biopsy
Thoracotomy

LC Staging
CT with contrast: TAP
Cerebral RMN or CT
PET CT (skull base to knees or
ALK and ROS 1 whole body)
mutations Mediastinoscopy
Biomarkers EBUS , EUS NCCN Guidelines Version 4.2017
Non-Small Cell Lung Cancer - NCCN
Evidence BlocksTM
 Reference diagrams for 2009 TNM staging system of lung cancer.

2011 by American College of Chest Physicians

Lababede O et al. Chest 2011;139:183-189

T

Lababede O et al. Chest 2011;139:183-189

 TNM Staging of Lung cancer - ediia a 7-a
(2009)
Tumor Extension T
TX Primary tumor cannot be assessed, or the TU is proven by the
presence of malignant cells in sputum or bronchial washing but is
not visualized by imaging or bronchoscopy

T0 No evidence of primary tumor

Tis Carcinoma in situ

T1 Tumor 3 cm in greatest dimension, surrounded by lung or visceral pleura,

no bronchoscopic evidence of invasion, more proximal than the lobar bronchus
(not in the main bronchus)
superficial spreading of tumor in the central airways (confined to the wall of the
trachea or mainstem bronchus

T1a Tumor 2 cm in the greatest dimension

T1b Tumor > 2 cm but 3 cm in the greatest dimension

The 7th Edition of TNM in Lung Cancer: What Now?By Peter Goldstraw Journal of Thoracic Oncology: June 2009 - Vol 4 - Issue
6 - pp 671-673
 T Extension
Tumor > 3 cm but 7 cm or tumor with any of the following:
T2 Invades visceral pleura
Involves the main bronchus 2 cm distal to the carina
Associated with atelectasis/obstructive pneumonitis extending to hilar region but not involving
the entire lung

T2a Tumor > 3 cm but 5 cm in the greatest dimension

T2b Tumor > 5 cm but 7 cm in the greatest dimension

T3 Tumor > 7 cm or one that directly invades any of the following:

Chest wall (including superior sulcus tumors), diaphragm, phrenic nerve, mediastinal pleura, or
parietal pericardium
Tumor in the main bronchus < 2 cm distal to the carina but without involvement of the carina
Associated atelectasis/obstructive pneumonitis of the entire lung
Separate tumor nodule(s) in the same lobe

T4 Tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea,
recurrent laryngeal nerve, esophagus, vertebral body, or carina;
Separate tumor nodule(s) in a different ipsilateral lobe
 Stadializarea N
Extensia tumorii la ganglionii regionali

NX Regional lymph nodes cannot be assessed

N0 No regional node metastasis

N1 Metastasis in ipsilateral peribronchial and/or ipsilateral hilar

lymph nodes and intrapulmonary nodes, including
involvement by direct extension

N2 Metastasis in the ipsilateral mediastinal and/or subcarinal

lymph node(s
N3 Metastasis in the contralateral mediastinal, contralateral
hilar, ipsilateral or contralateral scalene, or supraclavicular
lymph nodes
 Stadializarea M
Metastaze la distan
MX Distant metastasis cannot be assessed

M0 No distant metastasis

M1 Distant metastasis

M1a Separate tumor nodule(s) in a contralateral lobe;

Tumor with pleural nodules or malignant pleural (or
pericardial) effusion

M1b Distant metastasis including cervical

 CT - Dgn. and staging ( T )
T1 a < 2cm

T1b
2 -3 cm
T1 a
< 2cm
 NPS
IA T1 No Mo
 T2 >3cm - <7 T2a (3 5cm)
T2b (5 7 cm)
Invasion of the visceral pleura
main bronchi >2 cm from carina; Lobar
atelectasis

T2 a

AJCC Cancer Staging Atlas

 Lobar atelectasis
T2 a (3 -5 cm)

T2a

T2a IJsbrand Zijlstra, Otto van Delden, Cornelia Schaefer-Prokop and Robin Smithuis
The 7th Edition of TNM in Lung Cancer: What Now?By Peter Goldstraw Journal of Thoracic Oncology: June 2009 - Vol 4 - Issue 6 - pp 671-673
 T3 > 7 cm
T3 Nodules in the same lobe
Mediastinal invasion: heart, oesophagus,
tracheea, vessels, Recurrent N, vertebra
Nodules homolateral in other lobe

T4
 N staging and biopsy !!!
LN > 1 cm = usualy malign in the presence of a known TU
PET- CT, bronchoscopy, EBUS, MS, EUS

N2 ggl. mediastinali homolaterali

ggl. subcarineali

AJCC Cancer Staging Atlas

N3 - hilar LN, contralateral in mediastinum,
homo/contralateralsupraclavicular, scalenic

AJCC Cancer Staging Atlas

 Contralateral nodules
M1 a Pleural pericardial malign
efusion
 M1b
Adrenal glands

Vertebral dissemination - M1b

PET - CT
M1 Detection

MRI
Lung cancer - New TNM IJsbrand Zijlstra, Otto van Delden, Cornelia Schaefer-
Prokop and Robin Smithuis The radiology Asistant, Publicationdate:2-7-2010
 Endobronchial
Ultrasound Electromagnetic
EBUS TBNA Navigation
Transbronchial Needle Aspiration LN and peripheral mass biopsy

Bronhoscopy
biopsy, brosage
AFI AutoFluorescence imaging
NBI Narow Band Imaging Video -Assisted
Thoracoscopy
VATS
Endoscopic Ultrasound
EUS FNA Mediastinoscopy
Fine Needle Aspiration Thoracotomy
Bronchoscopy = indispensable
investigation
TU diagnosis

Endoscopic Staging

Sampling for histopathological confirmation

Endoscopic treatment (in some forms)

Restaging
 Prelevates
1.Bronchial biopsy
2.Brosage and bronchial aspirate
3.Broncho-alveolar (BAL)
4.Transbronchial /aspirate/ biopsy EBUS - TBNA (lung + LN)
+ sputum, pleural liquid, other
Specimen processing
Standard fixation 10% neutral buffered formalin (4% formaldehyde) is recommended [V, A]
Fixation time should be no less than 6 h, and no greater than 48 h [IV, A]
Sections for biomarker testing should ideally be cut immediately before analysis [IV, A]
Cytology samples (cellblocks, stained direct smears or liquid-based preparations) can be used reliably to
detectEGFRmutations and ALKrearrangements [III, A]. At this time, a cell block is the most widely applicable
cell source
The same pathologist should, if possible, review all available TU material from the same patient including
biopsies and cytology specimens to select the most suitable for biomarker analyses [IV, A]
A pathologist should be involved in sample preparation for DNA extraction [V, A]
Enrichment of samples by micro- or macrodissection to maximise TU cell content before DNA extraction is
recommended [III, A]
K.M. Kerr, L. Bubendorf,ESMO Consensus Guidelines: Pathology and molecular biomarkers for non-small-cell lung cancer, Ann Oncol (2014) 25 (9): 1681-1690

Betz BL, Dixon CA, Weigelin HC, Knoepp SM, Roh MH. The use of stained cytologic direct smears for ALK gene rearrangement analysis of lung adenocarcinoma. Cancer
Cytopathol. 2013;121:489499.
Transbronchial needle aspiration
TBNA

Dgn of Solitary Pulmonary Nodule IA

Cytology and histopathology of
Peripheral and mediastinal mases, LN
N staging and restaging
Guideline
Fluoroscopy
CT
EBUS
EMN
EBUS
TBNA
 Cell-block preparation from
EBUS-TBNA samples is a simple
way to provide additional
information in LC diagnosis

Analysis of cell blocks increases

the diagnostic yield by nearly
seven per cent and allows for
genetic analysis in a sixty per
cent of the patients with
metastatic adenocarcinoma

Contribution of cell blocks obtained through endobronchial ultrasound-guided transbronchial needle aspiration to the diagnosis
of lung cancer, Jos Sanz-Santos, Pere serra, at al BMC Cancer. 2012; 12: 34
 EMN
CT 3 plans with 3D reconstruction
Electromagnetic field GPS
coordinates
Bronchoscopy with distal sensor
Biopsy of Lymph nodes, peripheral
masses
 Pulmonology Clinic Tg Mures
2000 bronchoscopies/510 suggestive LC
246 biopsies with histopathological
confirmation from central TU (48,2%)
NSCC - squamous 57.52% 1.77
CC scuamos
NSCC - adenocarcinoma 12.4
5.3
22.12% Adenocarcin
oma
Large cell 5.31%
22.1 Large cell
57.5
SCC small cell 12.39%
Sarcoma 1.77% SCCC
 Guidelines for deciding which patients should have EGFR and
ALK biomarker testing.*
The goal is to match patients with approved drugs that target
those mutations.
Type of Lung Cancer Guidelines for Biomarker Testing

Testing for the EGFR and ALK mutations at the time of

Stage I, II, or III adenocarcinoma diagnosis is encouraged, but the decision should be made
on an individual basis with your physicians

Stage IV adenocarcinoma, or adenocarcinoma that has

recurred or progressed after an initial diagnosis of stage I,
Tumors should be tested for EGFR and ALK mutations
II, or III lung cancer in patients who were not previously
tested

If a tumor is completely removed and there is no

adenocarcinoma component, testing for EGFR and ALK
mutations is not recommended
If the specimen is from a more limited sampling
Any stage squamous cell lung cancer or small cell lung
technique, such as a biopsy, testing may be performed in
cancer
cases showing only squamous or small cell lung cancer
cells. This is because it is possible that a tumor may have
adenocarcinoma cells mixed in that were missed by the
biopsy
 Diagnostic algorithm for molecular testing of small biopsy or cytological
specimens in non-small cell lung cancer patients

Biopsy samples, cytology material, surgically resected

tumour. Whilst samples for FISH require a minimum number
of assessable TU cells, and both RT-PCR and NGS techniques
depend to mRNA or DNA quality and quantity, ALK IHC may
be read on a very small number of cells.

K. M. Kerr , L. Bubendorf , M. J. Edelman Second ESMO consensus conference on lung cancer: pathology and molecular biomarkers for non-small-cell lung cancer Ann Oncol (2014) 25
(9): 1681-1690

Guideline Recommendations for Testing of ALK Gene Rearrangement in LC: A Proposal of the Korean CP Pathology Study GroupHyojin Kim, Hyo Sup Shim, Lucia Kim

Kerr KM. ALK Testing in Non-Small Cell Lung Carcinoma: What Now? J Thorac Oncol 2014;9:593-595.