Lung cancer

Gabriela Jimborean
UMF Tg. Mures
Pulmonology Clinic
 Cancer statistics, 2017

LC morbidity
2020
• The incidence may increase to 15 million
2030
• Explosion - new cases - 27 million

Cancer statistics, 2017, Volume: 67, Issue: 1, Pages: 7-30, First published: 05 January 2017, DOI: (10.3322/caac.21387)
 Cancer statistics, 2017

LC mortality

II. Prostate CC

I. LC

II. Breast CC

Cancer statistics, 2017, Volume: 67, Issue: 1, Pages: 7-30, First published: 05 January 2017, DOI: (10.3322/caac.21387) GLOBOCANk
 LC – extraordinary severity
• At the time of diagnosis only 20-25% are operable/curable
• 50% of patients aged 45 to 65 (very active people)

7 of 8 patients are asymptomatic long time, establishing the diagnosis in advanced

stages TNM of invasive complications

Without treatment, most of cases die within the first year after diagnosis

 5 years survival very low - 15% for all forms including treated (except "solitary
pulmonary nodule" > 80 -90% - st. IA - T1 N0 M0)
 Age gets younger
 % of women is growing F: B ----1: 5 ( by women smoking “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
Environmental factors
1. Cigarette smoking 85-90% of LC in smokers (Relative risk 20-30x )
– Active and pasive (second hand, third hand smoking)
– Persistent smoking in LC patients increased
risk for
– Second primary cancer, posttreatment
complication
– Decrease quality of life, reduced survival
– Other tobacco – related condition (CV, COPD)
Active and passive smoking
• The risk correlates with:
– No of cigarettes during life = Year PACKS
– Type cigarettes, filter, deep of inhalation
– The age at starting smoking
↓ risk LC is very slow – it decreases in
15 y after smoking cessation
but does not touch the low risk of
non-smokers
 Other risk factors
1. SMOKING
2. Radon 222 exposure
3. Indoor cook stoves , bio mass
4. Other exposures asbestos, silica, arsenic, heavy metals
5. Exposure to other cancer-causing agents in the workplace. ...

Host factors
• Family history
• Specific genetic polymorphisms or mutations
• Chronic lung disease with inflammation
(Fibrosis, COPD, TBC , pneumoconiosis)
 Histological types
of LC
• Non small cell lung cancer NSCLC 85%
– Adenocarcinoma – 35 - 40%
– Squamous CC – 40%
– NSSLC probable squamous CC
– NSCLC, probably adenocarcinoma
– NSCLC - NOS
– Carcinoid tumor
– Large cell carcinoma – 5 -10%
– Other – adenoid cystic, mucoepidermoid

• Small cell carcinoma

All types of LC are
smoking related
 LC Screening

Screening
= Detection of LC in persons with RISK factors
In the absence of symptoms or signs of lung cancer (If symptoms – diagnosis, staging and
treatment

Smoking cessation – counseiling, NRT + varenicline

Low-dose CT (LDCT) 100–120 kVp, 40–60 mAs or less ( 1/year or 1 /2years

Risk factors group for screening

• Smoking history especially after 20 PY
• Smoking exposure (second-hand smoke)
• Radon, occupational exposure
• Cancer history
• Family history of lung cancer in first-degree relatives
• Disease history (COPD or pulmonary fibrosis, low lung
function)
• Lung cancer survivors
 LC Screening by LDCT
Advantages of LDCT screening Disadvantages of Screening
• Decreased LC mortality with 20% when

compare with chest xray (NLST - National Lung • Anxiety of test findings
ScreeningTrial) • False-positive results
• Increase Quality of life
• False-negative results
• Reduction in disease-related morbidity
• Radiation exposure
• Improvement in healthy lifestyles
• Cost
• Smoking cessation

• Reduction in anxiety/psychosocial burden

• Discovery of other significant health risks (eg,

thyroid nodule, silent CAD, early renal cancer,

aortic aneurysm, breast cancer)

 Clinical examination
Symptoms and signs: nonspecific, varied, small intensity
• 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 – 1.) pulmonary, 2). extrapulmonary (general and metastatic)
Symptoms ++++
Very suggestive Risk factors
• History of smoking
• History of occupational exposure (carcinogens)
• Old age
Hemoptysis
History of a prior neoplasia in the subjects and relative
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 ˂
• Dyspnea • Pain - pleural invasion
• Post obstructive pneumonia (fever) • Recurrent pneumonia - bronhoscopy
• Repeated pneumonia - Bronchoscopy
• Localized wheezing -! Bronchoscopy
• Pain
• Consolidation
• Atelectasis

Asthenia, weight loss, loss of appetite,

pallor
Fever - may be the obstructive
pneumonia
Intrathoracic extension (2)
Locoregional tumor extension
T3 - chest wall, pleura, phrenic nerve
T4 – mediast., diaphragm, heart invasion
- recurrent N (dysphonia)
- great vessels (Sup Cave Vein Sy - edema, cyanosis)
- trachea, carina (dyspnea, stridor)
- esophagus (dysphagia) (IIIB)
- simpatethic chain - S Claude Bernard Horner
(miosis, enoftalmy, palpebral ptosis)
Lymph node extension – N

Inoperabile
N3 or N2 + T3 + T4
 Extra thoracic non metastatic symptoms (3)
• General symptoms - nonspecific

• Peripheral/central neuropathies

• Blood
• Anemia, polycythemia

• Recurrent thrombophlebitis

• Digital clubbing

• Glomerulonephritis
• Endocrine sy
• Hyperkalemia

• Ectopic secretion of PTH, ADH

• Hyper secretion of ACTH

 Dissemination (4)

Extrathoracic dissemination
CNS 47% - MRI, CT
Bones 35% - Scintigraphy, PET - CT
Liver 22%
Adrenal glands 15% Abdominal US, CT, PET - CT
Thoracic dissemination
• Pericardial effusion = M1a (TUS)
• Malignant pleural extension with cytology - M1a (TUS)
• Lymphatic obstruction - chylotorace - M1a (TUS)
• Contralateral lung nodules M1a – CT, PETCT
European Guidelines for Cancer NSCC: ESMO
Clinical Recommendations for diagnosis, treatment and follow-up 2018

American guides NCCN guidelines - National Comprehensive Cancer Network Version

– 2018, NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines
® 2.2018 nccn.org

Correct Staging of LC
+ histopathological confirmation
+ TU biomarker

= Components of ensuring the

quality 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, robotic biopsy 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.

T1a – 0-1
T1 T2b - 1 -2
T3c - 2 -3

3 -4
4 -5

5 -7

T4

©2011 by American College of Chest Physicians

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

T

M1c

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

Lung - Cancer TNM 8th edition
Onno Mets and Robin Smithuis,
 Staging TNM 8 2017 th

Clinical - cTNM
Imagistic - iTNM
– Contrast CT
– MRI – cerebral in symptomatic patients
– PET – CT
– TUS/cardiac, cervical, abdominal US

Patologic - pTNM • FINAL TNMStaging

• Mediastinoscopy • HP confirmation
• VATS
• EBUS
Staging after treatment - yTNM
 TNM staging and pretreatment histology,molecular
genotype, immunophenotype

• Criteria in LC staging have to assign the higher possible classification

(biopsy from the lesion that can confirm the highest stage (from meta or
mediastinal LN)
• Patients with high suspicion of a st. I - II (clinic, imagistic) eligible for
surgical resection do not require pre-surgical TU biopsy (costly, time-
consuming) but LN biopsy for N staging
• Continued development of molecular and biomarker analysis: EGFR, ALK,
RAS, MET exon 14 alterations, HER2 mutations, and RET gene
rearrangements
• Continued development liquid biopsy (help find cancer at an early stage)
(near FUTURE !!!!)
 1. Circulating TU nucleic acids
Liquid biopsy 2.
3.
Apoptoic CTC
Circulating TU Cells (CTCs)
4. Exozomes
5. Circulating TU microemboli
6. Endothelial TU cells
7. Speciphic mutations
8. TU antibodies

Blood

. Zhuo Zhang,1 Nithya Ramnath,2,3,* and Sunitha Nagrath, Current Status of CTCs as Liquid Biopsy in Lung Cancer and Future Directions, Front Oncol. 2015; 5: 209.
2. Nilsson RJ, Balaj L, Hulleman E, van Rijn S, Pegtel DM, Walraven M, et al. Blood platelets contain tumor-derived RNA biomarkers. Blood (2011) 118(13):3680
3. Gevensleben H, Garcia-Murillas I, Graeser MK, Schiavon G, Osin P, Parton M, et al. Noninvasive detection of HER2 amplification with plasma DNA digital PCR. Clin Cancer Res (2013) 19(12):3276
4. Thierry AR, Mouliere F, El Messaoudi S, Mollevi C, Lopez-Crapez E, Rolet F, et al. Clinical validation of the detection of KRAS and BRAF mutations from circulating tumor DNA. Nat Med (2014) 20(4):430–
5.10.1038/nm.3511
 T1 b
T1a 0 - 1cm 1 - 2cm

T1c
2 -3 cm
 NPS
IA1,2,3 – T1a,b,c, No Mo
Surgery
Survival at 5 years
77 – 92%

Girvin F,JP Ko - Pulmonary Nodules: Detection, Assessment and CAD, AJR 2008, vol 191, 1057 - 1069
Size (˃ 3cm 97% Malignant)
Contour NPS
Calcification
Cavitation Increase over time
CT, CT-iv, PET-CT
(Risk of malignancy TD 20 - 400 days)
Substance loading. of contrast

Yankelevitz DF, Reeves AP, Kostis WJ et al – Small PN: volumetrically determined growth rates based on CT evaluation. Radiology 2000;217:251–6 ;
1.Soubani AO - The evaluation and management of the SPN PMJ 2008; 84:459-466
T2 3cm - <5cm
T2a (3 – 4cm)
T2b (4 - 5 cm)

TU invades the visceral pleura

main bronchi> 2 cm carina
lobar atelectasis

T2 a

AJCC Cancer Staging Atlas

T2 a: 3 -4 cm T2 Lobar athelectasis
+bronchial sign + details for surgery
(crossing the slit → pneumectomy)

T2b:4 -5 cm

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
 5 - 7 cm
T3 Nodules in the same lobe
Chest wall, pericardium
 Tu Pancoast
T3

T3

RMN

Revisions to the TNM Staging of Non–Small Cell Lung Cancer: Rationale, Clinicoradiologic Implications, and Persistent Limitations1 Arjun Nair,Maria J. Klusmann, Kirupa H.

Jogeesvaran, Sisa Grubnic, Siobhan J. Green, Ioannis Vlahos, RadioGraphics 2011; 31:215–238
TU ˃ 7 cm
- Invasion mediastinum, diaphragm, heart,
esofagus, carina, trache, vessels, recurent nerve,
Vertebra, Nodules in other lobe, homolateral

T4
N - nodes

N1 – Homolateral LN or
in hilum
• 10 – 14 R

N2 Homolateral mediastinal N3 - Contralateral mediastinal

or subcarineal LN or hilar contralateral,
scalene or supraclavicular
CT does not differentiate benign with malignant LN > 1 cm =
usually malignant in the presence of a known TU
→ PET- CT, EBUS, EUS

N2 LN homolateral mediastinali
ggl. subcarineali

T3N2
AJCC Cancer Staging Atlas
T2bN2
N3 N3 - Contralateral mediastinal LN or hilar
contralateral, scalene or supraclavicular

AJCC Cancer Staging Atlas

N3

Ultrasound image
IJsbrand Zijlstra, Otto van Delden, Cornelia
Schaefer-Prokop and Robin Smithuis
 M1 detection

RMN

Lung cancer - New TNM IJsbrand Zijlstra, Otto van Delden, Cornelia Schaefer-
Prokop and Robin Smithuis – The radiology Asistant, Publicationdate:2-7-2010
M1a
Contralateral nodules
Pleural nodules
Malignant pleurisy / pericarditis
Pleurale M1
 M1b M1 C hepatic, CSR and vertebral
1 meta extrathorax CSR

M1c - multiple vertebral M1

M1c
 PET – CT
• Non-invasive diagnosis and differential
dgn. between benign and malignant
masses by assessing vascularization
and metabolic activity (fixation of
contrast agent 18 DFG)
Indications
• Staging TNM (small M1, bony, lymph
nodes)
• Screening for primary TU when we are
in the presence of a metastasis
without etiology
Standardized Uptake Value = SUV
Semi-quantitative of FDG fixation
Radioactivity in tissue
SUV =
Injected dose / body weight

Soft tissue ~1
Malignity >2
Mediastinum ~1.5
Liver ~2 CNS ~ 8-10

Urine ~15-50 Tonsile ~ 3

Myocardium 2-7
PET - CT
PET - CT
 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;121:489–499.
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, José Sanz-Santos, Pere serra, at al BMC Cancer. 2012; 12: 34
 Mesothelioma

Advanced Pancoast

Pancoast Tobias
 Pulmonology Clinic Tg Mures (2017 – 2018)
2000 bronchoscopies/510 suggestive LC
246 biopsies with histopathological confirmation from central TU
(48,2%)

• NSCC - squamous 57.52% 1.77

5
• NSCC - adenocarcinoma .
12.4 CC scuamos
3
22.12% Adenocar-
cinoma
• Large cell 5.31% Large cell
• SCC small cell 12.39% 22.1 57.5 SCCC
Sarcoma
• Sarcoma 1.77%
 Treatment
Avoid risk factors
Early detection
Smoking cessation

Interdisciplinary team for

diagnosis and complex treatment
 Principles of treatment
“right patient for the right drug/technique”

• Stages I, II and IIIA (maximum T2N2 Mo, T3,T4 N1Mo)

– Initially benefit from Surgery (TU resection + LN exploration/
resection than neoadjuvant CTE)

– Med. Inop: SABR "stereotactic ablative radiotherapy (SABR)"

followed in “positive margins” by radiotherapy/ chemotherapy.
– ~~ T extension: "wedge resection", segmentectomy or lobectomy
+ st. I VATS technique possible
– Neoadjuvant chemo/postsurgery chemo will be added to Stage
IB, II and IIIA surgical patients
• T3-4N2 (IIIB), T1-2N3 (IIIB), T3-4N3 (IIIC)

= radio + chemo + Immunoterapy therapy without curative surgery

• St. IV – EGFR, RAS, ALK, BRAF, PDL1 detection

– Targeted theraphy and immunotherapy
– Systemic therapy for advanced stages - Platinum based
CHEMO upon histology
– Stereotactic surgery for brain M1
Restaging – yTNM, rTNM
– + laser/stent endobronchial therapy, brachiTE
– Reresection, RTE, SABR
 Palliative care
• Palliative care = approach to patient/family/caregiver-centered

health care that focuses on optimal effective management of

pain and other distressing symptoms, while incorporating

psychosocial and spiritual care according to patient/family

needs, values, beliefs, and cultures.

• The goal of palliative care

– to anticipate, prevent, and reduce suffering

– to support the best possible quality of life for patients/families/

caregivers, regardless of the LC stage or the need for other therapies.

– Palliative care can begins at diagnosis.