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5-Diagnosis, Paraclinical and Staging and of Lung Cancer - Alexandra, Gabi, Gabriela
5-Diagnosis, Paraclinical and Staging and of Lung Cancer - Alexandra, Gabi, Gabriela
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).
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).
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).
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).
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.
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
M - Distant Metastasis
M0 No distant metastasis
M1 Distant metastasis
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
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