Diagnosis of Lung Cancer

The diagnosis of lung cancer is of paramount importance since it allows

physicians to determine the histological type and stage of the cancer
along with the best treatment options that could be implemented. A
number of factors need to be considered when beginning the diagnostic
evaluation – time, risk of procedures and patient’s fitness. Time is of
grave concern because a delay in diagnosis may limit treatment options
and worsen the prognosis of the patient. In this case, investigations that
provide both diagnostic and staging (and sometimes symptomatic
treatment) may be more beneficial in preventing unnecessary delays.
Furthermore, the risks of individual procedures need to be considered
and be proportionate to the benefits (5). Moreover, the diagnosis of
cancer must recognise the individuality of the disease and take in
consideration of the patient’s overall well-being and ability to tolerate
various diagnostic and treatment procedures.
The diagnostic workup for lung cancer begins with the initial evaluation
of the patient followed by histological confirmation of the diagnosis. The
cancer must then be staged in order to evaluate the extent of the
disease and finally an analysis of the patient’s functional status is
performed with a view to treatment possibilities (1, 4).

Initial Evaluation
Medical History and Physical Exam
When a physician is approached by a patient, there may be no signs or
symptoms of the disease, or it may be discovered via screening.
Contrastingly, a patient may visit the doctor with specific complains that
indicate the existence of a malignancy. During this first visit, it is the
physician’s responsibility to perform a thorough evaluation of the
patient and to listen intently to all of his/her complains. It is essential to
correctly interpret all the symptoms the patient presents with and
determine any possible risk factors (6). In doing so, this could raise the
suspicion of a malignancy and rule out other pulmonary disorders.
A detailed history and physical examination is extremely vital as it not
only guides subsequent diagnostic and staging studies, but also provides
information on the patient’s general health, which is crucial for the
development of a rational management plan (4).
If the outcome of the history and physical examination suggest a
malignancy, further diagnostic procedures are ordered.
Blood Test
A blood test does not diagnose a cancer but instead gives certain
indications of the patient’s overall health status (6).
A complete blood count can provide information regarding the number
of all blood cells (red blood cells, white blood cells and platelets) that are
present in the blood. From this information we can deduce whether the
patient suffers from any illness (e.g. anaemia, infection, etc). White
blood cells, also known as leucocytes, are of immense importance as an
elevation in number can indicate malicious invasion by a pathogen or
malignancy.
Blood chemistry tests can also be performed and involve the indirect
assessment of the bone marrow, liver and kidney function as well as the
evaluation of any metabolic abnormalities such as hyponatremia (which
could be caused by SIADH) or hypercalcemia (potential cause could be
hypercalcemia syndrome in SCC) (4). Liver function tests, for example
aspirate aminotransferase (AST), alanine aminotransferase (ALT),
gamma-glutamyl transferase (GGT), prothrombin time (PT)/international
normalized ratio (INR), and alkaline phosphatase level can indicate
towards an advanced disease involving hepatic and bone metastasis
respectively (13).This test can indicate towards the existence of a
malignancy but other modalities must be used for further evaluation.

Imaging Modalities
Imaging studies are performed to assess symptoms that cannot be
explained by physical examination. It also allows staging of the disease in
patients with known or suspected lung cancer (4). Imaging tests can be
done before or after the diagnosis of lung cancer for various reasons
such as:
 To evaluate suspicious areas that might be cancerous
 To appreciate the extent of the disease
 To determine if treatment is working
 To look for any relapse of cancer

Chest X-ray
A plain chest x-ray is the cheapest and one of the first investigative steps
when there is suspicion of lung cancer (3). For patients with a very poor
general condition, or those who refuse any kind of treatment, it can
sometimes be the only investigation providing both the tumor
specificities (location, extension, complications) as well as the lymph
nodes assessment (8..lect). The radiograph may reveal an abnormal
nodule (<3cm) or mass (>3cm) opacity surrounded completely by lung
parenchyma consistent with lung cancer. However, this procedure is
limited as it does not confirm whether the opacity is benign or
malignant. In general, if lung nodules are less than 8mm in diameter
(assumed benign), repeat scans are performed in 6 to 12 months, with
further evaluation if the nodule increases in size. If nodules are found to
be greater than 8 mm, further workup is guided by the probability that
they are malignant (4).

Figure 3 – Poorly circumscribed right lower lobe opacity.

Source: Medscape

Computer Tomography (CT) Scan

A CT scan obtains detailed cross sectional
images of the region being examined and
shows the exact size, shape and position
of the tumour alongside any enlarged
lymph nodes, which would suggest
extension of the disease (6). In lung
cancer a CT scan of the chest and
abdomen should be performed to include
assessment of the liver and adrenal glands
(common sites for metastasis). This
procedure can simultaneously assess the Figure 4 – Contrast-enhanced CT scan showing large
left lung hilar mass with invasion of left pulmonary
primary tumour and its specificities, artery.
locally advanced disease (mediastinal Source: Medscape

involvement) and distant metastasis, thereby speeding up the diagnosis

process (4).
Magnetic Resonance Imaging (MRI) Scan
MRI scans are usually performed to provide detailed information about
the extension of the disease as oppose to the visualization of the
primary tumour and its surroundings. MRI scans are most often
performed to look for possible spread of cancer to the brain and spinal
cord (6). It provides a slightly better image than CT scans via its ability to
contrast between high and low fat content tissues (T1 and T2 weighted
sequences) (9). MRI scans have certain advantages over CT scans such as
better visualisation of soft tissue contrast, detecting invasion by the
tumour and multiplanar imaging capability which proves essential for
superior sulcus tumours (Pancoast tumours) (9). It may also be the
choice of investigation in individuals who have contraindication to the
use of contrast for CT scanning (lect..8) However, in some cases MRI
scans may be preferred less due to certain contraindications (patient’s
with pacemakers) and the lengthy and costly process (9).

Positron Emission Tomography (PET) Scan

Positron emission tomography (PET) is an imaging method which relies
on the increased metabolic activity of the tumour for detection (lect..8).
A radiotracer, fluorodeoxyglucose (FDG) is injected into the blood of the
patient. Since cancerous cells multiply and grow faster than normal cells,
they absorb large amounts of this radioactive sugar which then
reproduces a 3-D image of its functional process on a PET scanner (6).
Often a PET scan is combined with a CT scan which allows examination
of both the elevated function of cancerous cells and their exaggerated
anatomy (6). This test can also be used to evaluate uncertain abnormal
areas on other imaging tests as well as the spread of the cancer to
regional lymph nodes and extrathoracic sites for example, liver, adrenal
glands, and bones (4, 6). However, PET/CT is not very useful in
determining metastasis to the brain as all brain cells consume significant
amounts of sugars (glucose), similar to cancerous cells (6). Furthermore,
PET is not recommended in patients with a small (<2cm) peripheral lung
lesion with absence of all other abnormalities, and in patients already
known to have metastatic disease (4). Since FDG-PET has a false positive
rate of about 10%, it is important to obtain pathological confirmation of
malignancy before making therapeutic decisions (4).
Figure 5 – Lung Cancer: Coronal PET shows abnormal areas of increased metabolic activity in the left
hilar and left adrenal regions consistent with hilar tumour with left adrenal metastasis.
Source: Medscape

Histopathological Diagnosis
Although experienced physicians can often diagnose the type of lung
cancer based on clinical presentation and radiographic appearance, an
adequate tissue sample is imperative to optimize the diagnosis and plan
treatment (2). Frequently, the results of imaging studies are not
conclusive since they only identify abnormalities that may be malignant,
but cannot definitely diagnose cancer. It is therefore crucial to obtain
samples to perform histopathological diagnosis to confirm the
malignancy (4). These samples can include lung secretions (sputum or
phlegm cytology), fluid accumulated around the lung (thoracocentesis)
or from a suspicious area using a needle or surgery
(biopsy/bronchoscopy) (6).

Sputum Cytology
Mucous coughed up from the lungs is known as sputum and is examined
microscopically to observe if it contains cancerous cells. This test mainly
reveals cancers that are located in the major airways of the lung (6).
Centrally located endobronchial tumours can exfoliate malignant cells
into the sputum (13) and thus by examining the sputum cytologically, it
is possible to discover signs of malignant growth. However, sputum
cytology does not provide reliable distinction between different
histological types and subtypes of lung cancer (13). Moreover, although
a false positive rate is only about 1%, a false negative rate is as high as
40%. Therefore, to achieve diagnostic accuracy, rigorous specimen
sampling and preservation techniques are required (13). The best
method would be to collect three samples in the early morning
consecutively over three days. The samples must be obtained in an
airtight container and sent to the microbiology laboratory as soon as
possible.

Thoracocentesis
Fluid accumulated around the lungs, called pleural effusion, can occur
during lung cancer via invasion of the pleura. Physicians can perform a
manoeuvre, called thoracocentesis, to both diagnose the abnormality
and symptomatically treat the patient. For this procedure, the skin is
numbed using local anaesthetic and a hollow needle is inserted one
intercostal space below the top margin of the effusion at the mid
scapular line. The collected fluid is sent for cytological examination to
determine whether it contains any cancerous cells or not (6).

Biopsy
There are various types of biopsies that can be performed in order to
collect tissue samples for histopathological diagnosis. Choosing the
correct site to biopsy is crucial as it not only provides confirmation of
malignancy and staging of the disease, but also tumour material for the
analysis of molecular markers (for example, epidermal growth factor
receptor - EGFR, anaplastic lymphoma kinase - ALK and Kirsten rat
sarcoma viral oncogene - KRAS) used in the selection of targeted therapy
(4). Generally, the biopsy of a metastatic site is preferred over the
primary tumour since it provides conclusive evidence of metastatic
spread (4).
Types of biopsies include fine needle biopsy (FNB), core needle biopsy
(CNB) and transthoracic needle biopsy.
 Fine needle biopsy: a syringe with a thin, hollow needle is used to
aspirate cells and small tissue fragments from the suspicious
location (6).
 Core needle biopsy: a large bore needle is used to remove one or
more small cores of tissue. Because core needle biopsy samples
are larger, it is often preferred over fine needle biopsy (6).
An advantage of needle biopsy is that it doesn’t require a surgical
incision. However, the drawback to this procedure is that the
 sample obtained is very minimal, especially in FNB, and may
sometimes be inadequate enough to reach a diagnosis (6).
 Transthoracic needle biopsy: In cases where the suspected tumour
is located on the outer surface of the lung, a transthoracic biopsy
needle is inserted through the skin of the chest wall. This form of
biopsy is performed under local anaesthetic and is guided by
either CT or fluoroscopy (moving image) (6). This method is the
first-line procedure for diagnosis of peripheral tumours (2). A
possible complication of this procedure could involve air leaking
out of the biopsy site and into the pleural space, thereby creating
a pneumothorax. However, whether the leak is small or big, it
easily resolves within a few days (6).

Bronchoscopy
In situations where FNB, CNB and transthoracic needle biopsy are not
viable options for collection of tumour tissue, a more invasive
procedure, called bronchoscopy, may be used. This investigative
procedure allows the physician to simultaneously visualise the suspected
cancer and take a biopsy. A lighted, flexible fibre-optic tube, called a
bronchoscope, is passed through the mouth or nose into the bronchi.
Once the suspected tumour is located, small instruments can be passed
down the bronchoscope to obtain a tissue sample for histological
examination (6). The tumour can also be rubbed with a small brush
(called bronchial brushing) or rinsed with sterile saline (called bronchial
washing) to obtain samples for cytological evaluation.
Transtracheal FNB or transbronchial FNB can also be performed by
passing the hollow needle through the bronchoscope into the trachea or
bronchi to achieve a sample (6). Bronchoscopy allows confirmation of
primary tumours with a sensitivity of 0.88 for central tumours and 0.78
for peripheral tumours, and can also provide information for T-staging
and cytology samples for N-staging of lung cancer (1).

Staging of the Disease

Once there is confirmation of lung cancer via histopathological diagnosis,
the extent and stage of the disease needs to be established. This is of
paramount importance and guides the therapeutic course. There are
various modalities that look for the spread of lung cancer surrounding
the primary location, in the lymph nodes and other distant locations.
Endobronchial Ultrasound
Ultrasound uses sound waves to create images of structures around the
body. A small microwave-like instrument called a transducer gives off
sound waves that bounce off bodily tissue and return to form an image
on the computer screen (6). In endobronchial ultrasound, the
bronchoscope is fitted with a transducer and passed via the trachea into
the bronchi to view the lymph nodes and mediastinum. If any
abnormality (enlarged lymph nodes) is seen on EBUS, a hollow needle
can be passed through the bronchoscope to obtain a biopsy, which can
then be tested for malignancy (6). This procedure is extremely useful as
it collectively allows visualisation of the tumour and its surrounding
structures as well as an opportunity to obtain a biopsy for staging of the
disease.

Endoscopic Esophageal Ultrasound

This procedure is similar to EBUS but instead of passing a bronchoscope
through the trachea, an endoscope is guided through the mouth and
into the esophagus. The esophagus lies just behind the trachea and is
proximal to certain thoracic lymph nodes. Thus, an ultrasound can be
performed via the esophagus to detect any lymphatic or structural
invasion by the cancer. If any abnormality is seen, a biopsy can be taken
through the endoscope and sent for histological examination (6).

Mediastinoscopy
Assessment of the mediastinum is an important aspect of staging
patients with potentially resectable lung cancer. Metastatic spread to
mediastinal lymph nodes is generally considered a contraindication to
primary surgical resection (4). In the past, the only procedure available
to define mediastinal lymph node metastases before surgery was
mediastinoscopy (4). However, less invasive methods such as
endobronchial ultrasound (EBUS)-guided and endoscopic ultrasound
(EUS)-guided are now more commonly used (4).
Mediastinoscopy allows visualisation of the mediastiunum in detail to
estimate the extent of the cancer invasion. It is performed in the
operating room by a surgeon under general anesthesia. A small cut is
made 1cm above the suprasternal notch and a thin, hollow, lighted tube
is inserted behind the sternum but in front of the trachea. Biopsies can
be obtained from suspicious areas or enlarged lymph nodes by passing
instruments through this tube. The samples are then sent for histological
examination (6).
Mediastinotomy
In some instances mediastinoscopy cannot access certain lymph nodes.
In these cases a mediastinotomy is performed. This procedure is similar
to mediastinoscopy and only differs by size and location of the incision.
An incision of about 2 inches is made between the second and third ribs
on the left hemithorax beside the sternum, under general anaesthesia
(6). A lighted tube is then inserted into the thorax to visualise and obtain
a biopsy of the malignancy, after which samples are sent for histological
examination.

Thoracoscopy
Thoracoscopy is a minimally invasive procedure that involves making an
incision on the side of the chest wall while the patient is under general
anaesthesia in the operating room. A thin, lighted tube is inserted
through the incision to view the pleural space. This method can allow for
drainage of excess pleural fluid, visualisation of the pleural space and
lymph nodes for any abnormalities and removal of a part of the lung in
some early-stage cancers. If certain areas cannot be reached, a larger
incision may need to be made, which is called a thoracotomy (6). This
procedure is also known as video assisted thoracic surgery (VATS) (6).

Bone Marrow Aspiration and Biopsy

This investigative modality is utilised in the event of cancer spread to the
bone marrow, which is the soft inner part of long bones and responsible
for haematopoiesis (blood cells production). This test was mainly used in
patients thought to have early (limited) stage SCLC whose blood tests
suggests bone marrow metastasis. In recent years, however, PET scans
are used more often for this purpose (7).
Both bone marrow aspiration and biopsy are performed simultaneously
and samples are most often collected from the back of the pelvic bone
(7). Bone marrow aspiration is performed by cleaning and numbing the
skin at the hip. A thin, hollow needle is then inserted into the bone and a
syringe is used to aspirate a small amount of liquid bone marrow (7).
Bone marrow biopsy is done just after the aspirate is collected. A larger
needle is inserted deeper into the bone and small pieces of bone and
marrow are collected (7).

Brain Imaging
Advanced stages of lung cancer have an affinity to brain metastasis,
especially in SCLC. It is therefore essential that brain scans be performed
in order to evaluate the stage of the disease and determine possible
therapeutic options. MRI scans are more sensitive than CT scans in
detecting brain metastasis, particularly smaller lesions and those in the
posterior fossa (4).

Bone Scan
Radionuclide bone scans are intended for
the detection of bone metastasis from
primary lung cancer. Since PET scans also
perform this function, this test is rarely
used. It is only when all other modalities
are unclear and there is clear indication of
bone involvement (bone pain) that this
procedure is utilised (4, 6).

Figure 6 – Lung cancer: Whole body nuclear bone scan with

anterior and posterior images revealing multiple abnormal
areas of increased radiotracer activity in the pelvis, spine,
ribs and left scapula. Findings consistent with bone
metastasis
Source: Medscape

Diagnostic approach for possible Lung Cancer

Figure 1 - Diagnostic approach for possible lung cancer.

Source: Medscape
 Staging
The American Joint Committee on Cancer (AJCC) generated a system to
classify all lung cancers based on the size of the primary tumour (T
descriptor), lymph nodes involvement (N descriptor) and distant
metastasis (M descriptor) (3, 6). Moreover, AJCC also devised a stage
grouping of lung cancer in accordance with the TNM system. Once the T,
N and M categories are determined, this information is combined in a
process called stage grouping to assign an overall stage (6). This stage
grouping assists with choice of treatment and estimation of prognosis
(3). The most recent and updated version (8th edition) of the TNM
classification was introduced in January 2017 by the International
Association for the Study of Lung Cancer (IASLC).

TNM Classification
T-Descriptor
Tumour evaluation determines the T descriptor of lung cancer staging.
This evaluation is most often performed by contrast-enhanced CT but in
certain situations, especially Pancoast tumours, MRI can be used to
deliver a more detailed view of the lesion and its surroundings (1).

N-Descriptor
Lymph node involvement is frequently measured by contrast-enhanced
CT. However, since its sensitivity is only between 51% and 64% and
specificity lies between 74% and 86%, it is unreliable as a sole
investigative procedure (1). PET or PET-CT is currently the most accurate
non-invasive procedure for mediastinal N-staging with a sensitivity of
74% and a specificity of 85% (1). It is possible to perform a biopsy of
suspected lymph nodes to achieve a precise N-staging (1). There are
fourteen groups of lymph nodes located in the thorax which are further
categorised into five stations. A nodal map outlining all the groups and
stations is shown below.

M-Descriptor
Distant metastasis of lung cancer is the most major obstacle against
treatment with curative intent. The most common location of lung
cancer metastasis is brain, bones, liver and adrenal glands (1). Although
the patient’s history, clinical findings and lab results may provide
important clues about distant metastasis, confirmation is mandatory for
M-staging (1). The best suited modalities to locate distant metastases
are contrast-enhanced cranial CT or MRI, bone scintigraphy,
ultrasonography, CT or MRI of the liver and adrenals, and PET or PET-CT.

Figure 2 – Nodal Map

Source: The International Association for the Study of Lung Cancer (IASLC)
TNM Staging System
The IASLC (International Association for the Study of Lung Cancer)
8th edition lung cancer staging system was introduced in 2017 and
supersedes the IASLC 7th edition. It describes the TNM staging system
when evaluating lung cancer and further classifies the disease into 4
major stages.

T, N, and M Descriptors for the 8th edition of the TNM Classification of

Lung Cancer

T - Primary Tumour
Category Subcategory Description
TX Primary tumour cannot be assessed, or
tumour proven by the presence of
malignant cells in sputum or bronchial
washings but not visualized by imaging or
bronchoscopy
T0 No evidence of primary tumour

Tis Carcinoma in situ:

Tis(AIS): adenocarcinoma
Tis(SCIS): squamous cell carcinoma
T1 Tumour 3 cm or less in greatest dimension,
surrounded by lung or visceral pleura,
without bronchoscopic evidence of invasion
more proximal than the lobar bronchus (i.e.,
not in the main bronchus). The uncommon
superficial spreading tumour of any size
with its invasive component limited to the
bronchial wall, which may extend proximal
to the main bronchus, is also classified as
T1a.
T1mi Minimally invasive adenocarcinoma

T1a Tumour 1 cm or less in greatest dimension

T1b Tumour more than 1 cm but not more than

2 cm in greatest dimension
T1c Tumour more than 2 cm but not more than
3 cm in greatest dimension
T2 Tumour more than 3 cm but not more than
5 cm; or tumour with any of the following
features. T2 tumors with these features are
classified T2a if 4 cm or less, or if size cannot
be determined; and T2b if greater than 4 cm
but not larger than 5 cm.
 Involves main bronchus regardless of
distance to the carina, but without
involving the carina
 Invades visceral pleura
Associated with atelectasis or obstructive
pneumonitis that extends to the hilar
region, either involving part of the lung or
the entire lung
T2a Tumour more than 3 cm but not more than
4 cm in greatest dimension
T2b Tumour more than 4 cm but not more than
5 cm in greatest dimension
T3 Tumour more than 5 cm but not more than
7 cm in greatest dimension or one that
directly invades any of the following:
parietal pleura (PL3), chest wall (including
superior sulcus tumours), phrenic nerve,
parietal pericardium; or associated separate
tumour nodule(s) in the same lobe as the
primary
T4 Tumors more than 7 cm or one that invades
any of the following: diaphragm,
mediastinum, heart, great vessels, trachea,
recurrent laryngeal nerve, esophagus,
vertebral body, carina; separate tumour
nodule(s) in a different ipsilateral lobe to
that of the primary
N - Regional Lymph Nodes
NX Regional lymph nodes cannot be assessed

N0 No regional lymph node metastasis

N1 Metastasis in ipsilateral peribronchial and/or

ipsilateral hilar lymph nodes and
intrapulmonary nodes, including involvement
by direct extension
N2 Metastasis in ipsilateral medaistinal and/or
subcarinal lymph node(s)
N3 Metastasis in contralateral mediastinal,
contralateral hilar, ipsilateral or contralateral
scalene, or supraclavicular lymph node(s)

M - Distant Metastasis
M0 No distant metastasis

M1 Distant metastasis

M1a Separate tumour nodule(s) in a contralateral

lobe; tumour with pleural nodules or
malignant pleural or pericardial effusion.
Most pleural (pericardial) effusions with lung
cancer are due to tumour. In a few patients,
however, multiple microscopic examinations
of pleural (pericardial) fluid are negative for
tumour, and the fluid is non-bloody and is
not an exudate. Where these elements and
clinical judgment dictate that the effusion is
not related to the tumour, the effusion
should be excluded as a staging descriptor.
M1B Single extrathoracic metastasis in a single
organ and involvement of a single distant
(non-regional) node
M1c Multiple extrathoracic metastases in one or
several organs
 Stage Grouping for the 8th Edition of the
TNM Classification for Lung Cancer

STAGE T N M
Occult TX N0 M0
carcinoma
0 Tis N0 M0
IA1 T1mi N0 M0
T1a N0 M0
IA2 T1b N0 M0
IA3 T1c N0 M0
IB T2a N0 M0
IIA T2b N0 M0
IIB T1a N1 M0
T1b N1 M0
T1c N1 M0
T2a N1 M0
T2b N1 M0
T3 N0 M0
IIIA T1a N2 M0
T1b N2 M0
T1c N2 M0
T2a N2 M0
T2b N2 M0
T3 N1 M0
T4 N0 M0
T4 N1 M0
IIIB T1a N3 M0
T1b N3 M0
T1c N3 M0
T2a N3 M0
T2b N3 M0
T3 N2 M0
T4 N2 M0
IIIC T3 N3 M0
T4 N3 M0
IVA Any T Any N M1a
Any T Any N M1b
IVB Any T Any N M1c
 Variations between the 7th and 8th IASLC Lung Cancer Staging System
The TNM staging system for lung cancer has experienced crucial change
resulting in a revised, more accurate evaluation and staging system for
lung cancer.

Figure 3 - Variations between the 7th and 8th IASLC Lung Cancer Staging System
Source: Radiology Assistant

Veterans Administration Lung Study Group Staging System

In small cell lung cancer, the Veterans Administration Lung Study Group
(VALSG) classification system is sometimes used alongside the TNM
system to stage SCLC for treatment purposes. It classifies SCLC into a
limited disease (confined within a single tolerable radiation field) or an
extensive disease (extended outside of a single hemithorax) (2). This 2-
stage system aids in the determination of the treatment of choice.

Limited Stage
In this instance the cancer is only limited to one side of the chest and
can therefore be treated with a single radiation field. Cancer that has
spread to involve the supraclavicular lymph nodes is also considered to
be in the limited stage as long as they are on the same side as the
primary tumour. In the case of mediastinal lymph nodes, their
involvement may also account as a limited disease even though they
may be closer to the adjacent hemithorax. Studies show that only one-
third of patients with SCLC present during the limited stage of the
disease (7).

Extensive Stage
This stage describes lung cancer that has spread far beyond the primary
tumour location, to the other hemithorax, lymph nodes and to other
regions of the body. As SCLC is a very aggressive lung cancer, most
individuals (2 out of 3) present with the cancer in the extensive stage (7).

Functional Evaluation

After completing the initial and histological diagnosis along with the
staging of the disease, it is necessary to evaluate the patient’s functional
capacity to withstand appropriate treatment. This mainly applies to
individuals that qualify for surgical resection. Most lung cancer patients
are current or former smokers with a high probability of chronic
obstructive pulmonary disorder (COPD) and coronary heart disease
(CHD), conditions that are associated with increased surgical morbidity
and mortality (11). Candidates for lung resection require standard
preoperative evaluation taking multiple factors into consideration; age,
cardiac and pulmonary function, blood gas assessment and exercise
testing. This evaluation is of paramount importance to reliably assess the
risk of operation (12).

Age
Advanced age, usually defined as more than 70 years, is associated with
complications following pulmonary resection. However, this increased
risk is mainly a result of comorbidities in the elderly rather than the
surgical procedure itself (11). It is therefore possible for individuals over
70 years of age with a good performance status (karnofsky score 70
points) and intact cardiopulmonary reserve to have a long-term survival
comparable with younger surgical candidates (11). Consequently, elderly
patients in a good state of health must not be excluded from surgery
solely on the basis of their age (11).
 Figure 7 – Performance status scales for patients with cancer
Source: Medscape

Pulmonary Evaluation
When a tumour is considered resectable, curative resection should be
attempted. In advanced tumours, substantial amounts of pulmonary
parenchyma may need to be resected leading to permanent loss of
pulmonary function. Thus, it is essential to evaluate the preoperative
pulmonary function of the patients and assess whether they can
withstand the intervention, and estimate the postoperative risks
involved (11).
There have been multiple parameters for pulmonary risk assessment
prior to any surgical intervention. Currently the emphasis is on the
determination of predicted postoperative forced expiratory volume in
the first second (ppoFEV1) and predicted postoperative carbon
monoxide diffusing lung capacity (ppoDLCO) (12). All functional
parameters must be measured when the patients are at their best. For
pulmonary function tests this means an intensive course of
antiobstructive therapy and inhalation therapy with bronchodilator
drugs, chest physiotherapy and smoking cessation (11).
ppoFEV1:
Predicted postoperative FEV1 along with ppoDLCO is calculated on the
number of functioning pulmonary segments that will be removed during
surgery. This test is most accurately obtained using a split perfusion scan
with intravenous Tc-99m, or with quantitative CT (11). There is a set
formula for precise calculation (11):
 ppoFEV1 = preoperative FEV1 x (1- functional contribution of the
parenchyma to be resected)
This same formula has been used for ppoDLCO and ppoVO2max
(predicted postoperative maximum oxygen volume consumption) (11).
In all instances, a value less than 40% has been associated with an
elevated perioperative pulmonary risk (11).
Many studies have shown the role of ppoFEV1 in predicting
postoperative complications and selecting patients for surgery (12).
Markos et al reported that half the patients with a ppoFEV1 <40% died
in the perioperative period. Moreover, it has also been confirmed that
perioperative risk increases significantly when the ppFEV1 is <40% of
predicted normal (12)
ppoDLCO:
Similar techniques as ppoFEV1 are used to obtain a ppoDLCO. Recent
studies have reported that patients with <40% ppoDLCO had a mortality
rate of 23% (12). Moreover, a linear inverse correlation exists between
pulmonary complications and ppoDLCO, with patients with ppoDLCO
<30% at an increased risk (80%) of pulmonary complications (12).
Furthermore, a reduced ppoDLCO has been shown to be a predictor of
cardiopulmonary morbidity and mortality not only in patients with
reduced FEV1 but also in those with normal respiratory function (12).
According to these findings, recent guidelines recommend the
measurement of DLCO in all candidates for lung resection regardless of
their ppoFEV1 (12).

Cardiac Evaluation
Patients with lung cancer often have both pulmonary and cardiac
disease as a result of cigarette smoking, and therefore are potentially at
an increased risk for perioperative cardiovascular complications,
including ventricular fibrillation, pulmonary edema, complete heart
block, cardiac arrest and cardiac death (12). The risk of these major
cardiac events following lung resection is reported to be 3% (12). In
many instances, it may be advised for pulmonary surgical candidates to
undergo prophylactic coronary revascularization prior to surgery even
though they may not otherwise need such a procedure. However this
does not appear to reduce perioperative risk (12).
Brunelli et al utilised the thoracic revised cardiac risk index (ThRCRI) to
estimate a patient’s risk of perioperative cardiac complications after
major anatomic lung resection. This tool weighed 4 factors associated
with major cardiac morbidity with different weights - history of coronary
artery disease, 1.5 points; cerebrovascular disease, 1.5 points; serum
creatinine level >2mg/dl, 1 point; and pneumonectomy, 1.5 points. The
resulting aggregate, ranging from 0 to 5.5, showed that high points in
the ThRCRI resulted in an increased risk of 23% of major cardiac events
occurring postoperatively, comparable to just 1.5% risk in those with the
lowest score (12).
There are numerous cardiac anomalies associated with varying degrees
of increased perioperative cardiovascular risk, some of which are
outlined below (8):
Major:
• Unstable coronary syndrome
• Recent myocardial infarction
• Severe angina pectoris (grade 3, 4)
• Uncompensated cardiac failure
• Significant arrhythmias
• Atrio-ventricular block
• Severe valvulopaties
Intermediate:
• Medium angina pectoris (grade 1, 2)
• History of myocardial infarction (Q wave present)
• Compensated cardiac failure
• Diabetes mellitus
Minor:
• Age
• ECG: LVH, LBB, ST-T disorders
• Atrial fibrillation
• History of stroke
• Uncontrolled hypertension

Blood Gas Measurements

The predictive value of arterial blood gas measurements for functional
operability is less than certain (11). Arterial oxygen tension doesn’t
indicate any rise in risk for pulmonary resections (11). But an oxygen
saturation value less than 90% is a predictor of perioperative
complications in standard lung resection interventions (8). In contrast,
arterial carbon dioxide tension more than 45mmHg represents an
increased risk. However, this value alone should not exclude patients
from surgery (11).
Exercise Testing
All parameters discussed so far measured specific aspects of a patient’s
functional reserves. However exercise testing is an overall parameter for
the assessment of cardiopulmonary reserves via determination of a
patient’s fitness (11). During exercise, oxygen consumption, carbon
dioxide production and cardiac output all increase, reflecting the
capabilities of the lung, heart and vasculature in delivering oxygen to the
tissues (11). In the lung, exercise determines an increase in ventilation,
VO2 (maximum oxygen consumption), carbon dioxide excretion and
blood flow, similar to those experienced after lung resection (12). The
main emphasis is on the measurement of VO2max which qualifies for
resection up to pneumonectomy if it is more than 20ml/kg per minute or
more than 75% predicted. A value less than 10ml/kg per minute (or less
than 40% predicted) is generally prohibitive for any resection (11).
Bolliger et al outlined that the probability of developing complications
with a VO2max greater than 75% of predicted was only 10% whereas the
in patients with a VO2max less than 40% the risk was as high as 90%
(12). Most studies generally agree that a VO2max below 10-15ml/kg/min
is regarded as a high risk threshold for lung resection and values above
20ml/kg/min are safe for any kind of resection, including
pneumonectomy (12).
Numerous tests can be used for exercise testing which are either
classified as low-technology tests or high-technology tests (12).
Low-technology tests:
There are two main types of low-technology tests – shuttle walk test and
stair climbing test. 25 shuttles on the shuttle walk test indicates a
VO2max of 10ml/kg/min. Benzo et al reported that a cut-off of 25
shuttles had a positive predictive value (PPV) of 90% for predicting a
VO2max > 15ml/kg/min. The stair climbing test, on the other hand, is
frequently used. The ability to climb three or more flights of stairs and
five or more flights of stairs have been suggested as a safe indication to
undergo resections of a lobectomy and pneumonectomy respectively
(11). Other studies concluded that climbing 4.6 flights of stairs (83 steps,
15.35m) corresponded to a VO2max of 20ml/kg/min which has been
shown to qualify for a pneumonectomy (11). Brunelli et al also
suggested that climbing more than 14m qualified patients for major
resections without any further pulmonary function test (11).
High-technology tests:
High-technology tests include cardiopulmonary test with direct
measurement of the expired gases during incremental exercise on a bike
or treadmill (12). They are preferred over low-technology tests because
they can be easily reproduced, assess ischemia with online
electrocardiographic monitoring, and are short in duration (15-20
minutes) (11). Cardiopulmonary exercise testing (CPET) is the gold
standard test in preoperative evaluation of lung resection candidates
(12). It is performed in a controlled environment with continuous
monitoring of various cardiologic and pulmonary parameters. This test
should be performed in all patients with FEV1 or DLCO or both <80%
predicted and those with a significant history of cardiac disease (12).

Algorithms for the Functional Evaluation of

Lung Resection Candidates
Even though there are numerous tests to evaluate functional capacity,
many resections can be performed without any sophisticated tests. This
stresses the need for an algorithm for preoperative functional evaluation
(11). These algorithms are standardized guides to preoperative clinical
practice, thereby minimizing variation and inappropriate exclusion (12).
Patients follow successive steps of functional testing on the basis of cut-
off values until they qualify for resection or are deemed inoperable (11).
The most recent functional algorithm is the one proposed by the
American College of Chest Physicians (12) and is as follows:
Figure 8 - Algorithm for the assessment of the cardiorespiratory reserves of lung resection
candidates
Source: Lippincott Williams & Wilkins