Small lung nodule is a common problem in pulmonary practice. The definition of a classical solitary pulmonary nodule is a single, spherical, well-circumscribed, radiographic opacity less than or equal to 30 mm in diameter that is completely surrounded by aerated lung and is not associated with atelectasis, hilar enlargement, or pleural effusion. Ideally, the goal of diagnosis and management is to promptly bring to surgery all patients with operable malignant nodules while avoiding unnecessary thoracotomy in patients with benign disease. In fact, causes of solitary pulmonary nodules can be benign or malignant. In order to diagnose causes of solitary pulmonary nodules, we can use many different methods, including clinical symptoms, radiographic features, liquid biopsy, bronchoscopy, CT-guided fine-needle aspiration biopsy and surgery. Each method has its own value. It is very meaningful if we can diagnose these causes early. Based on these results, doctors can determine the strategy to manage disease.
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DIAGNOSIS OF SOLITARY PULMONARY NODULES:
AN UPDATED REVIEW
Dao Ngoc Bang 1 ; Ta Ba Thang 1 ; Do Quyet 2
SUMMARY
Small lung nodule is a common problem in pulmonary practice The definition of a classical solitary pulmonary nodule is a single, spherical, well-circumscribed, radiographic opacity less than or equal to 30 mm in diameter that is completely surrounded by aerated lung and is not associated with atelectasis, hilar enlargement, or pleural effusion Ideally, the goal of diagnosis and management is to promptly bring to surgery all patients with operable malignant nodules while avoiding unnecessary thoracotomy in patients with benign disease In fact, causes of solitary pulmonary nodules can be benign or malignant In order to diagnose causes of solitary pulmonary nodules, we can use many different methods, including clinical symptoms, radiographic features, liquid biopsy, bronchoscopy, CT-guided fine-needle aspiration biopsy and surgery Each method has its own value It is very meaningful if we can diagnose these causes early Based on these results, doctors can determine the strategy to manage disease
* Keywords: Solitary pulmonary nodule; Diagnosis
1 Causes and proportion of solitary
pulmonary nodules
The definition of a classical solitary
pulmonary nodule (SPNs) is a
single, spherical, well-circumscribed,
radiographic opacity less than or equal to
30 mm in diameter that is completely
surrounded by aerated lung and is
not associated with atelectasis, hilar
enlargement, or pleural effusion [1]
Causes of SPNs are very variety, with 2 main groups: benign or malignant
ones ( table 1) The estimated prevalence
of each etiology varies among different populations Even among screening studies of smokers who are at increased risk of malignancy, the number of malignant nodules is small Among 12,029 nodules found in a large Canadian study, only 144 (1%) were malignant [2]
1 103 Military Hospital
2 Vietnam Military Medical University
Corresponding author: Dao Ngoc Bang (bsdaongocbang@yahoo.com.vn)
Date received: 24/07/2019
Date accepted: 23/08/2019
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Table 1: Differential diagnosis of SPNs [2]
Infectious granuloma (atypical mycobacteria, coccidioidomycosis,
histoplasmosis, tuberculosis)
80%
Benign Arteriovenous malformation; intrapulmonary lymph node; sarcoidosis Rare
Malignant
Characteristics of each cause are
extremely different, including clinical
symptoms and paraclinical changes
Depending on the characteristics of SPNs,
doctors should apply some suitable
methods in diagnosis and management
2 Diagnosis of SPNs
* Characteristics of risk factors:
The probability of malignancy can be
assessed clinically or by quantitative
predictive models as falling into 1 of 3 risk
categories: very low probability (less than 5%), low/moderate probability (5% to 65%),
or high probability (greater than 65%) The most commonly used model estimates the probability of malignancy using six independent predictors: smoking history, older age, history of extrathoracic cancer more than five years before nodule detection, nodule diameter, spiculation presence, and upper lobe location
An online calculator is available at http://reference.medscape.com/calculator/ solitary-pulmonary-nodule-risk [3]
Table 2: Calculating the malignancy probability of a pulmonary nodule [3]
Cancer history 1: if patient has a history of extrathoracic cancer diagnosed more than five
years before nodule detection (otherwise = 0) Diameter Diameter of the solitary pulmonary nodule in mm
Location 1: if nodule is located in the upper lobe (otherwise = 0)
Smoking history 1: if patient is a current or former smoker (otherwise = 0)
Spiculation 1: if spiculation is present (otherwise = 0)
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* Radiographic features and PET/CT:
Incidentally found SPNs are most
commonly discovered on CT (computed
tomography) scans Although some may
be seen on chest radiographs, a CT-scan
affords superior detail for evaluating
specific characteristics of the nodule Of
particular importance is a thorough review
of all previous imaging to assess both
changes in size and the rate of
change over time Numerous studies had
demonstrated that increasing nodule size
corresponding with increasing risk of
malignance: a nodule smaller than 5 mm,
less than 1% malignancy risk; a nodule
of 5 - 9 mm, 2 - 6% malignancy risk;
a nodule of 10 - 20 mm, 18% malignancy
risk; a nodule 20 mm or larger, more than 50% malignancy risk Signs of growth on serial imaging are highly suggestive of malignancy The growth rate of an SPN
is also used to evaluate the potential for malignancy, with most malignancies doubling in volume between 20 and 400 days A solid SPN that has been stable for more than 2 years is likely to be benign,
as is a subsolid nodule that has been stable for more than 3 years Attenuation
of the nodule on CT imaging may be characterized as solid or subsolid, with subsolid lesions further divided as pure subsolid and part solid Although solid lesions are more common, subsolid lesions are more likely to be malignant [4, 6]
Table 3: Radiologic features suggested benign or malignant SPNs [4]
Calcification Concentric, central,
or popcorn pattern
Typically noncalcified or eccentric calcification
Doubling time Less than one month or
CT examinations of the thorax performed to follow lung nodules should use a low-radiation technique Techniques to reduce low-radiation dose are important, given the frequency with which follow-up CT examinations are performed
Table 4: Summary of management pathway for SPNs by ACCP guideline [6]
Size
(5 - 65%)
High (> 65%)
surveillance*
PET/CT and optional biopsy/resection
Staging for treatment
(*: Timing and term of CT surveillance depend on nodule size and appearance; ACCP: American College of Clinical Pharmacy)
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Table 5: Summary of management pathway for single SPNs by Fleischner Society
guideline 2017 [5]
Risk for lung cancer Size (volume)
6 - 8 mm (100 - 250 mm3) CT surveillance*
> 8 mm (> 250 mm3) CT surveillance* with optional PET/CT, biopsy and/or resection
(*: Timing and term of CT surveillance depend on nodule size and appearance)
National Comprehensive Cancer Network
(NCCN) guideline proposes different cut-off
for size, follow-up interval and surveillance
term depending on the appearance of the
nodule, e.g., solid, part-solid, or non-solid
Follow-up methods proposed by the
Fleischner Society (2017) vary depending
on whether the nodule is solid or sub-solid
American College of Clinical Pharmacy
(ACCP) guidelines outline similar
methodology; follow-up methods mainly
depend on nodule appearance, nodule
size, and risk or probability of malignancy
[3] If the nodule appears highly suspicious
for malignancy, non-surgical biopsy or
surgical resection should be carried out
Most guidelines recommend non-surgical
biopsy or surgical resection when the
nodule develops a solid component The
BTS suggests resection in cases where
the nodule grows more than 2 mm in
maximum diameter even if the nodule
retains a pure ground glass appearance
PET/CT: Studies have shown that the
sensitivity and specificity of PET for the
diagnosis of malignant lesions can reach
87% and 83%, respectively However,
PET also has its shortcomings Firstly,
PET is not sensitive for nodules smaller
than 8 - 10 mm in diameter For patients
with in situ adenocarcinoma, carcinoids and mucinous adenocarcinoma, PET may provide a false negative result, and false positive findings may occur in patients
(sarcoidosis or rheumatoid nodules) or in
a status of infection (fungal or mycobacterial infections) [5, 6]
* Liquid biopsy:
Liquid biopsy, which analyzes biological fluids especially blood specimen to detect and quantify circulating cancer biomarkers, have been rapidly introduced and represents
a promising potency in clinical practice of lung cancer diagnosis and prognosis Unlike conventional tissue biopsy, liquid biopsy is non-invasive, safe, simple in procedure, and is not influenced by manipulators’ skills Notably, some circulating cancer biomarkers are already detectable in disease with low-burden, making liquid biopsy feasible in detecting early stage lung cancer [7, 8] Currently, varieties of circulating cancer biomarkers are available for liquid biopsy including tumor-associated antigens (TAAs), tumor-associated autoantibodies (TAAbs), circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), microRNA (miRNA),
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exosomes and so on TAA markers
detectable in serum like carcinoembryonic
antigen (CEA), carbohydrate antigen (CA)
125, CA199, neuron specific enolase
(NSE), cytokeratin 19 fragment 21-1
(Cyfra 21-1) and squamous cell carcinoma
(SCC) are hard to be used in detection
of early lung cancer with poor sensitivity
and specificity However, serum TAAbs,
autoantibodies against overexpressed,
mutated, misfolded, or aberrant autologous
cellular antigens, may be associated with
unique advantages in identifying individuals
with early lung cancer That has been
theoretically supported for reasons, which
include: immuno-surveillance occurs in
the early phase of cancer immuno-editing
process and autoantibodies may be
detectable in early stage of lung cancer;
TAAbs can be present at high titers even
tumor mass is low and are stable in blood
CTCs are cancer cells directly shed off
from primary tumor sites or metastatic
sites and float in the circulation, which can
be isolated as either single cells or
clusters Ct-DNA is cell-free fragments of
DNA shed into the bloodstream by tumor
cells undergoing necrosis, apoptotic or
active secretion events It is tumor specific
and provides molecular clues about
fragmented DNAs of tumor cells and
their specific mutations Quantitative and
qualitative analysis respectively on the
amount and biological characteristics of
ct-DNA provide real-time evaluations for
diagnostic and prognostic assessments
There is some other source of liquid
considered for early detection of lung
cancer likes exosomes, MiRNAs and so
on [7]
* Bronchoscopy:
Development of technologies like virtual bronchoscopy (VB), electromagnetic navigation bronchoscopy (ENB), ultra-miniature (UM) radial probe EBUS (RP-EBUS) and ultrathin bronchoscopes has been a boon for bronchoscopists [9]
- Traditional flexible bronchoscopy: Many
studies have proved that this method has
a low sensitivity of the lesion with the size less than 2 cm, especially when the lesion
is peripheral [9]
- Virtual bronchoscopy and virtual
bronchoscopy navigation: VB utilizes
non-contrast CT of the chest to generate three-dimensional virtual image of the airways, which closely mimics the actual airways As selection of endobronchial pathway to the lesion can be a potential major source of error in reaching a peripheral lesion VB guidance can be very useful in selecting the appropriate airway Virtual bronchoscopic navigation (VBN) involves navigation to the peripheral lesion-using pathway based on airways leading to lesion planned using VB and simultaneous aligning and superimposition
of virtual views on the actual bronchoscopic views [9]
- Ultrathin bronchoscopy: Small
bronchoscopes with an outer diameter of 2.8 - 3.5 mm are considered ultrathin although a formal definition doesn’t exist The small size of ultrathin bronchoscopes allows better maneuverability and they can visualize deeper into the tracheobronchial tree and can reach up to the 6 - 8 generation bronchi The ultrathin bronchoscopes are usually used with image guidance technology
to reach close to the peripheral lesions [9]
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- Radial probe EBUS: The UM
RP-EBUS has a 20 MHz transducer at the tip
which rotates 360° perpendicular to the
direction of insertion and obtains real-time
high-resolution images of the structures
surrounding the airways The RP-EBUS
can be inserted directly through the
working channel of bronchoscopes or can
be used with a guide system or through
extended working channel (EWC) of
electromagnetic navigation systems into
the target bronchus to confirm appropriate
localization of the area of interest Once
the lesion is confirmed, the guide system
is fixed in place and RP-EBUS is removed
and various sampling instruments can be
advanced through the guide system to
sample the lesion Based on systemic
reviews and meta-analysis, the overall
sensitivity of RP-EBUS for diagnosis of
peripheral lesions is around 70% although
there is considerable heterogeneity in
nodule characteristics and variable use of
additional image guiding technology in
included studies Major limitation of the
technique is operator dependence [9]
bronchoscopy: The ENB system works
similar to the global positioning system
(GPS) of the vehicles Like VB, the ENB
technology requires thin-section CT to
create a virtual bronchial tree This CT is
performed prior to the procedure The
lesion is reviewed in the axial, sagittal,
and coronal planes and marked as the
target Endobronchial pathways to the
lesion are planned and marked using the
virtual airways Many of the studies of
ENB are small non-randomized single
center studies with yield diagnostic yields
ranging from 63% to 85% Significant
factors associated with higher sensitivity were larger nodule size, presence of bronchus sign, nodule visualization with RP-EBUS and so on [9]
* CT-guided fine-needle aspiration biopsy (FNAB):
FNAB is a common method for lung tissue biopsies in clinical settings, particularly for SPNs located close to the chest wall The diagnostic accuracy mainly depends
on an operator’s positioning and puncturing skills, in addition to the pathology technical level that may have a certain impact on the results With the established role of
CT screening for lung cancer, and the broad application of high-resolution CT, the SPN are increasingly detected In recent years, an important type of pulmonary nodules has gradually increased, namely the subcentimeter nodules, which refer to those with a diameter < 8 mm Although most SPN is benign, the pathology of the nodule is crucial to a patient with a history
of cancer even if the SPN is small and peripheral FNAB is a minimally invasive diagnostic method, with a high positive diagnostic rate, less injury and low cost;
so, it has been widely used in the routine diagnosis of SPN Diagnosis by FNAB on small nodules has the following features:
- Wide adaptation range: Except for central type lesions, the diagnostic rate of bronchoscopy on the peripheral type and diffuse lesions is little while FNAB can be applied both in central type lesions or peripheral type and diffuse lesions, as long as there is no apparent adhesion in blood vessels
- FNAB has a high accuracy: For lesions about 0.5 - 1 cm, it can also successfully conduct biopsy under CT guidance
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- High diagnostic accuracy: FNAB is
a well-established, useful procedure
However, the diagnostic accuracy of
FNAB depends on the size and location
of the lesion, as well as the guidance
technique, and decreases from over 90%
to 25% when the malignant nodule is
small (< 1 cm), and to 70% when the
lesion is benign
- High safety: Although FNAB is a safe
and reliable examination method, it is still
a traumatic investigation, so there are still
some complications The main complications
of FNAB mainly include pneumothorax
and haemorrhage According to literature
reports, the incidence of pneumothorax is
about 10 - 40% while the incidence of
pulmonary injury is about 26 - 33% [10]
* Surgery:
In the case of a high probability of
malignant pulmonary nodules (> 60 - 70%),
video-assisted thoracoscopic surgery
(VATS) is the recommended strategy, for
it satisfies the needs of both diagnosis
and further treatment With a benign result
from intraoperative frozen pathology,
only wedge resection will be needed
For malignant pathological findings,
surgical resection should be selected in
combination with systematic lymph node
dissection [10]
CONCLUSSIONS
The management of SPNs involves
both clinical and paraclinical assessment
including risk assessment, morphology
and histopathology of the nodule To
assess each characteristic, doctors should
apply different methods, with their own
advantages and disadvantages Full use
of newer techniques should play an important role in diagnosis and management
of SPNs
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