DIAGNOSTIC APPROACH

TO PATIENTS SUSPECTED
AS LUNG MALIGNANCY

Zen Ahmad
INTRODUCTIONS

Lung cancer or bronchogenic carcinoma, refers to

malignancies that originate in the airways or pulmonary
parenchyma, it is probably the most deadly disease
associated with tobacco use

Lung cancer remains the leading cause of cancer-related

mortality in the United States despite advances in
chemotherapeutic options and surgical technique

The evaluation of patients with suspected or known lung

cancer requires accurate and preferably rapid diagnosis
and staging to facilitate the optimal treatment regimen
INTRODUCTIONS
The 10 leading cancer types in the United States (2018)

234,030 persons were diagnosed ; 154,050 persons died of the disease

(CA Cancer J Clin 2018;68:7‐30. © 2018 American Cancer Society
Risk factors
Risk factors

Alberg AJ, Brock MV, Ford JG, et al. Chest. 2013;143(5 suppl):e1S-e29S.
 Clinical presentation
 A new onset cough, chest pain, hemoptysis and weight
loss are often the presenting features of lung cancer
 High degree of suspicion: a change in the character or pattern
of cough and a new onset hemoptysis in patients with established
tuberculosis or COPD
 Symptoms can be caused by:
• Primary tumor (e.g., cough, hemoptysis)
• Intrathoracic spread (e.g., Horner syndrome, SVC obstruction)
• Distant metastasis (e.g., bone pain)
• Paraneoplastic Syndrome

Asomaning K, Miller DP, Liu G, et al. Lung Cancer. 2008;61(1):13-20.

Imaging techniques

The aims of imaging are

 To locate the anatomical site of the lesion,
 To guide in obtaining tissue biopsy for confirmation
of diagnosis
 To stage the disease

Imaging and sampling procedures are commonly performed

concurrently for diagnosis and staging of lung malignancies.
Chest X-Ray
Certain tell-tale signs of malignancy on CXR include:
 Rib erosion
 ‘Golden S’ – Right upper lobar collapse with a right hilar central
mass forming a reverse S shape in PA view
 Signs of lobar or lung collapse
 Pleural effusion with fixed mediastinum
 Cannon ball or rounded opacities in lungs indicating metastasis
 Cavity (thick or irregular wall can be a cavitating malignancy)
A new opacity in a follow up CXR of a
patient with TB or COPD should also be
treated with high index of suspicion.
An attempt must be made to review any
previous X-rays of the patient and assess
the probable age and progression of the
disease
CXR view showing collapse of the right lung
upper lobe due to a central obstructing
mass. Due to the central mass, medial
portion of the minor fissure bulges
downwards and along with the collapsed
lobe laterally gives rise to the inverted 'S'
configuration
Pleural effusion with fixed Thick or irregular wallcavity can be a
mediastinum cavitating malignancy
Computed Tomography
 CT thorax is recommended for further evaluation of fi
ndings suggestive of lung cancer on CXR
 Contrast CT : to facilitate differentiation between a
mediastinal lymph node and vessel and to aid in
nodal staging
 CT findings suggestive of a lung malignancy include
mass like opacities or cavities with thick and irre
gular wall.
Computed Tomography
In CT thorax, must also be made to visualize:
1. Mediastinal invasion
2. Vertebral invasion
3. Nodule in other lung/ liver which signifies inoperability
4. Tracheal / main bronchus obstruction – which may warrant
an Endobronchial bronchoscopic intervention to maintain
bronchial lumen for symptom alleviation. A cancer that has
invaded trachea and carina is also inoperable.
Upper abdominal cuts should preferably be included in a CT
thorax to look for any metastatic lesions in the liver and adrenals
(two common sites of lung cancer metastasis).
N2 - Nodes
N2-nodes represent ipsilateral mediastinal
or subcarinal lymphadenopathy.
STAGING & BIOPSY

Histopathological confirmation of diagnosis of lung

cancer is mandatory for any form of therapy whether
surgery / chemotherapy or radiation therapy of lung
cancer.

Identifying the histopathological type of lung cancer also

aids in prognosis.
Selection of Biopsy Site
For selection of a biopsy site as well as for staging of lung
cancer, a careful evaluation of patient and review of all
radiological images is essential

Procedures for Histopathology and Cytopathology

Site Histopathology Cytopathology

Lung Bronchoscopic biopsy, transthoracic Sputum cytology, bronchos-

biopsy, surgical biopsy copic washing / brushing,
bronchoscopic needle aspi-
rates
Lymph node Surgical biopsy Transthoracic aspirates
EBUS TBNA or CT guided biopsy of Transbronchial aspirates
mediastinal lymph nodes

Distant metastasis Core needle biopsy (lliver, adrenal, Pleural fluid

bone) Needle aspirates (eg. Liver)
Bronchoscopy

 Bronchoscopy is an excellent diagnostic test as it also helps

in the staging of the disease (TNM staging) and obtaining a
specimen for biopsy
 A bronchial biopsy of a central lesion is easily obtained,
Alternatively brush smears of central lesions can be taken
 Bronchial wash and bronchioalveolar lavage are also useful
cytological tools in expert hands.
 A transbronchial biopsy can be attempted for a peripheral
lesion
Bronchoscopy
Pathology

 Lung cancer is classified by its histologic

appearance into small cell lung cancer (SCLC) or
non–small cell lung cancer (NSCLC)
 NSCLC is divided into adenocarcinoma, squamous
cell carcinoma, and large cell carcinoma
 NSCLC is sometimes poorly differentiated and only
distinguishable by immunohistochemical stains and
molecular testing
 The optimal choice of treatment relies on a complete
phenotypic and genotypic characterization of the
tumor
Combined PET-CT

 PET is an imaging technique that captures the level of metabolic

activity of different tissues
 FDG-PET is a good imaging modality with a reported sensitivity of 97%
 It can also be helpful in detecting metastatic lesions and lymph nodes
EBUS-FNA
 Endobronchial ultrasound (EBUS)
 To visualize the airway wall and adjacent structures
 Any lesion touching the trachea or main bronchi can be
visualized using this technique
 An EBUS guided transbronchial needle aspiration (EBUS-
TBNA) can be used for cytology
 Mediastinoscopy
 Complication rate of as high as 2-3%
 Unable to certain lymph nodes such as hilar (station 10,11,
12), para-aortic (st 6), or aortopulmonary window (st 5)
EBUS-FNA
 An alternative minimally invasi-
ve technique that complements
mediastinoscopy by its ability to
access lymph node stations 2,
3, 4, 7, 10, and 11

 EBUS is a bronchoscopic tech-

nique that utilizes ultrasound to
identify and permit real-time
ultrasound-guided needle
biopsy of paratracheal, hilar,
and interlobar lymph nodes
Schematic of the lymph node stations within the chest
Guidance Assisted Bronchoscopy

 Significant limitations to using bronchoscopy: inaccuracy

of bronchoscopy directed biopsy of lung nodules
 Electromagnetic navigational bronchoscopy (ENB) is now
able to overcome this limitation for select lesions that are
more than 1 to 1.5 cm in diameter
 This system marries CT imaging with bronchoscopy
allowing the physician to determine the position of the
bronchoscope and a special guidance catheter within the
lung of a patient
Cervical and Anterior Mediastinoscopy

 Mediastinoscopy is currently limited to patients in whom EBUS is

negative or not available
 Mediastinoscope can reach paratracheal and carinal nodes; may
reach paraoesophageal nodes; cannot reach interlobar nodes
 Mediastinoscopy involves an incision at the base of the neck
followed by the insertion of a mediastinoscope to permit sampling
of the paratracheal lymph nodes (stations 1, 2, 3, and 4) as well
as anterior subcarinal lymph nodes
 An extended cervical mediastinoscopy allows access to the para-
aortic lymph nodes (station 6).
Thoracentesis
 Pleural effusions with layer at least
1 cm on lateral decubitus CXR are
easily assessed for malignancy by
thoracentesis

 This procedure requires only local

anesthesia with 1% lidocaine and
the placement of a temporary
drainage catheter to remove the
available pleural fluid

 The procedure can be performed in

an outpatient setting and is gene-
rally well tolerated by the patient.
Video-assisted Thoracoscopic Surgery
(VATS)
 In this technique, a scope is
introduced to the pleura and the
lesion is directly visualized
 It is superior to any USG guided
as the lesion is directly visualized
and biopsy can be taken from the
lesion
 The diagnostic yield is about 98%
for malignancy and 100% for TB
 VATS or thoracoscopy is a surgical method that permits the sur-
geon to evaluate the pleural space and ipsilateral lymph nodes
Video-assisted Thoracoscopic Surgery
(VATS)

 The procedure requires general anesthesia, single lung

ventilation, and usually a short hospital stay but is usually
well tolerated with an average complication rate of 2%
 Thoracoscopy can also evaluate the pleural space for
malignancy in patients with pleural effusions that are
cytologically negative on repeated thoracentesis or in
patients with pleural abnormalities detected on CT
 VATS provides an alternative approach to anterior and
extended cervical mediastinoscopy for the evaluation of
lymph node stations 5 and 6
Biopsy Method Accessible Lymph Node stations

EBUS-FNA 2,3,4,7,10,11

EUS-FNA 4,5,7,8,9

Mediastinoscopy (cervical) 1,2,3,4,7 anterior

Mediastinoscopy anterior 5

Extended cervical mediastinoscopy 6

Ipsilateral hilar & mediastinal lymph nod

VATS
es
CT or USG Guided FNA
 CT or Ultrasound (USG) guided biopsy can be performed in
peripheral lesions
 It can be performed with a trucut biopsy needle under CT
guidance or ultrasound guidance
 When compared to CT guided biopsy, USG guided biopsy is a
real time biopsy with no radiation exposure
 USG guided biopsy has potential to provide same-day
confirmation of diagnosis of lung cancer
 The procedure is generally very well tolerated and can be
performed in an outpatient setting
Sputum Cytology

 The usefulness of sputum cytology is dependent on

the level of expertise of the examining pathologist
 Studies have shown that sputum cytology can
detect malignancy in 71% of central tumours and <
Chest Society. 2012;29(1):19-23.

50% of peripheral tumours

 A minimum of 3 samples should be examined to
increase yield.

Ammanagi AS. Chest. 2013;143(5 suppl):e1S-e29S.

The Role of Immunohistochemistry

 A widely available technique

 Can detect the druggable genetic alterations and for
the assessment of biomarkers for molecular-targeted
therapy
 Immunohistochemistry can be interpreted using fewer
tumor cells
 Classification of lung cancer into specific subtypes

Inamura K. Cancers 2018, 10, 72

TARGETABLE MUTATIONS IN LUNG
CANCER

The diagnostic evaluation of a patient with suspected

lung cancer includes 3 specific goals:
1. Does the patient have lung cancer and if so, what
type of lung cancer is present?
2. What is the pathologic stage of lung cancer?
3. If appropriate, are specific mutations or immunomodu-
latory targets present in the lung cancer that could be
targeted by a specific therapy?
Molecular diagnosis and immunohistochemistry has been
gaining importance due to development of targeted monoclonal
antibodies against certain receptors

Adenocarcinomas are known to be associated with

upregulation of specific receptors which can be targeted for
therapy.

An exciting and promising area of investigation is the use of a

blood sample or a “liquid biopsy” to assess for multiple
mutations.
TARGETABLE MUTATION

Epidermal Growth Anaplastic Lymphoma

Factor Receptor Kinase (ALK) –
(EGFR) Rearrangements

Kirsten Rat Sarcoma

Virus (KRAS)

Programmed death 1
C-ros Oncogene 1
(PD-1) / Programmed
(ROS1)
death ligand 1 (PD-L1)
3
Mutations in lung cancer
Percentage incidence of single tumour driver
mutations*

Mutations were found in

54% of tumours
22 completely tested by the
LCMC*
The three most prevalent
46 aberrant changes
detected were:
17 ● EGFR (ErbB1)
mutations
● KRAS mutations
● EML4-ALK
7 rearrangements
3

1. Vijayalakshmi R et al. Indian J Surg Oncol. 2011;2:178‒188.

2. Kris MG et al. J Clin Oncol. 2011;29:Abstract CRA7506 and oral
presentation.
3. Shigematsu H et al. Int J Cancer. 2006;118:257‒262.
4. Shaw AT et al. J Clin Oncol. 2009;27:4247–4253.
5. Marakami S et al. Lung Cancer. 2010;69:361–364.
* Data are taken from a prospective study by Lung Cancer
Mutation Consortium (LCMC); a total of 516 patients 37
with adenocarcinoma were tested
*Data are taken from a prospective study by Lung Cancer Mutation Consortium (LCMC); a total of 516 patients with adenocarcinoma
were tested
Molecular testing helped physician to make informed
decisions
 Histology guided chemotherapy

Chemo
•Benefit: <40%
Histology
•Systemic side effect

 Molecular testing guided target therapy

Target
Mol testing •Benefit: >60%
•Minimal side effect

Molecular testing is as important as therapy

38
Actionable targets and therapies in NSCLC

39

Adapted from Presentation of David Spigel at ASCO

2017.
4
The three most common mutations in NSCLC are found in
different types of patients

Mutation Prevalence Patient characteristics

Predominantly found in:
● Never-smokers
EGFR Overall prevalence: ● Women
(ErbB1) 10-40%
Tumours with adenocarcinoma histology
Prevalent in Asian patients
Predominantly found in:
Overall prevalence: ● Smokers
KRAS 8-24% ● Men
Nearly always found in adenocarcinomas
Predominantly found in:
● Non-smokers and light smokers
Overall prevalence: ● Younger patients
EML4-ALK 3-7% ● Men
Acinar growth pattern with or without signet-
ring cells
EGFR vs KRAS mutations are mutually exclusive such that they are not found in the same populations of NSCLC
patients
EML4-ALK rearrangements and EGFR mutations do not generally occur together but some NSCLC patients with EML4-
ALK have been shown to harbour concurrent EGFR mutations 40

1. Vijayalakshmi R et al. Indian J Surg Oncol. 2011;2:178‒188.

2. Shigematsu H et al. Int J Cancer. 2006;118:257‒262.
3. Sasaki GV et al. Cancer Res. 2011;71:6051‒6060.
 CONCLUSIONS

 Lung Cancer in Indonesia is one of country’s major

health problem, with high mortality rate
 Most patients made it into clinic late and diagnosed
above stage IIIA. Early screening must be done to get
patients early in their course of disease
 Immunohistochemistry plays a critical role in the classi
-fication of tumors into subtypes and for assessing bio
markers for timely and accurate therapeutic purposes
THANK YOU