Solitary Lung Nodule: The Impact
of Computed Tomography on Pre-Test Probability of Malignancy, Lung Cancer
Staging And Management
Aldo
Pezzuto, Raffaele Ratta, Yuri Errante, Carlo Cosimo Quattrocchi, Anna Maria
Frezza, Pierfilippo Crucitti, Giuseppe Tonini
Aldo Pezzuto, Department of Cardiopulmonary, Sant’Andrea Hospital,
Sapienza University, Via di Grottarossa 1035, 00189, Rome, Italy
Raffaele Ratta, Department of Oncology, University Campus Bio-Medico, Via
Alvaro del Portillo 200, 00128, Rome, Italy
Anna Maria Frezza, Giuseppe Tonini, Department of Oncology, University
Campus Bio-Medico, Via Alvaro del Portillo 200, 00128, Rome, Italy
Yuri Errante, Carlo Cosimo Quattrocchi, Center for Integrated Research in
Biomedicine and Bioengineering, Radiology, University Campus Bio-Medico, Via
Alvaro del Portillo 200, 00128, Rome, Italy
Pierfilippo Crucitti, Department of Surgery, University Campus Bio-medico, Via
Alvaro del Portillo 200, 00128, Rome, Italy
Correspondence to: Giuseppe Tonini, Department of Oncology, University
Campus Bio-Medico, Via Alvaro del Portillo 200, 00128 Rome, Italy.
Email: g.tonini@unicampus.it
Telephone: +39-06-225411201
Fax: +39-06-225411933
Received: January 25, 2014 Revised: April 18, 2014
Accepted: April 23, 2014
Published online: May 18, 2014
ABSTRACT
Lung cancer still represents the leading cause of cancer death in both
women and men with over a million deaths annually. It is often detected as a
lung nodule, a frequent finding in both in smokers and non smokers. The early
detection, accurate characterization, and appropriate management of pulmonary
nodules require a multidisciplinary approach, involving radiologists, medical
and radiation oncologists, pneumologists and thoracic surgeons.The purpose of
our review is to summarize the main characteristics of lung nodules, their CT
scan aspects (location, size, pattern and growth rate assessment) and the
establishment of the pre-test CT probability of malignancy that is essential to
guide management towards molecular non invasive tests and/or biopsy clinical
management. When the malignant nature is defined, CT imaging allows lung cancer
staging and guides the clinician for patient management.
© 2014 ACT. All rights reserved.
Key words: Lung; Nodule; CT; Smoke;
Carcinogenesis; Imaging; Biopsy; Patient management
Pezzuto A, Ratta
R, Errante Y, Quattrocchi CC, Frezza AM, Crucitti P, Tonini G. Solitary Lung
Nodule: The Impact of Computed Tomography on Pre-Test Probability of
Malignancy, Lung Cancer Staging And Management. Journal of Tumor 2014;
2(5): 129-135 Available from: URL:
http://www.ghrnet.org/index.php/JT/article/view/678
INTRODUCTION
Focal pulmonary
opacities large up to 5 mm in diameter are routine finding in smokers. Most of
them are benign, deriving from scars secondary to infectious diseases or
inflammation.
Aim of this review is to
discuss the origin, the clinical approach and the management of lung nodules in
different types of subjects.
STATE OF THE ART
Definition and nature of lung nodules
According to the
Nomenclature Committee of the Fleischner Society, a “solitary pulmonary nodule”
is a roundish structured lesion less than 3 cm in diameter, completely
surrounded by normal pulmonary parenchyma, while solitary lung lesions larger
than 3 cm in diameter are defined masses and often malignant[1]. Lung
nodules are spherical, not coin-shaped and not associated with atelectasis,
hilar enlargement or pleural effusion.
Nodular lesions recognise
several possible etiologies, both benign or malignant (Table 1).
Infections are one of the
leading cause of lung nodules. Infectious granulomas represent more than 80% of
benign pulmonary lesions, most of the times due to mycobacterial and fungal
organisms[2].
A further possible aetiology
is silicosis, either associated with tuberculosis or not[3]. Silicosis,
made of crystalline silica derived from occupational exposure, is a carcinogenic
condition. According to retrospective studies, pulmonary malignancies in
nodules of silicosis is established as 10% and the most frequent histological
type is squamous cell carcinoma. Small opacities (12 point scale) and large
opacities of different grade are the radiological findings useful to classify
silicosis according to the ILO classification.
The scar lesions, resulting
from a variety of infective, traumatic, environmental or occupational
exposures, can also promote the development of lung cancer, possibly through
mechanism of lymphatic drainage blockage and local pooling of carcinogens[4].
Tuberculosis often presents
as nodules, especially in its miliary expression[5]. The acute phase
proteins produced during the early phase of tuberculoid infection can result in
a lung scar. Other granulomatous infections include histoplasmosis,
aspergillosis, cryptococcosis, coccidioidomycosis. Infectious granulomas
account for more than 40% of benign nodules and they most often have a
well-defined smooth border. The coexistence of silicosis and tuberculosis in
miners accelerates the development of lesions.
Hamartomas account for 15%
of benign lesions[5]. They usually show a chondroid pattern of
calcification (central or diffuse) and may present a fat component in the
context of the lesion with negative Hounsfield units values, which is a
patognomonic finding.
Previous radiation therapy
and cigarette smoking increase the prevalence of scar lesions; smoke habit can
lead to the development of malignant lesions, especially if smoke intake
persists. Approximately 80% of lung cancers are associated to previous or
concomitant smoking habit and several carcinogenic mechanism have been
identified. Carcinogens contained in tobacco are a complex mixture of over
5,000 substances, including tobacco-specific N-nitrosamines, polycyclic
aromatic hydrocarbons, aromatic amines, aldehydes, phenols, volatile
hydrocarbons, nitro compounds, and other organic and inorganic compounds that
can damage cell structures (DNA, lipids and proteins) in both direct and
indirect ways[5].
Inflammation seems to play a
key role in the occurrence of lung cancers in smokers, being one of the first
step leading to the release of cancer promoting factors such as the nuclear
factor B (NF-B).
METHODS
Eligible articles
included English language papers published in peer-reviewed journals reporting
data on subjects with lung nodules. The choice included studies in vivo and in
vitro, screening programs, guidelines. The inclusion criteria were the
statement of smoking status, the age, risk of cancer. Papers referring to a
possible therapy for nodule reduction were also considered. The MEDLINE,
EMBASE, SCOPUS databases were systematically searched from inception to June
2013.
Clinico-radiological pre-test
probability of malignancy
The early detection,
accurate characterization, and appropriate management of pulmonary nodules
require a multidisciplinary approach, involving radiologists, medical and
radiation oncologists, pneumologists and thoracic surgeons.
From a clinical point of
view, older age, smoking status, smoking cessation status and positive history
for cancer have been recognized as independent predictors of malignancy in lung
nodules.
Growth rate assessment is an
important and cost-effective step in the evaluation of nodules, but it needs
follow-up over time, multiple radiological examinations and it is not well
accepted from the patients' side. Thus, methods to establish the pre-test
probability of malignancy have been developed, based either on Bayesian or on
multivariate logistic regression analyses[6]. However, none of these
methods have been shown to be superior to the clinical judgment of an expert
physician in predicting the probability of malignancy[7]. With the application
of these models that include clinical variables and gross nodule
characteristics such as size and location, patients may be classified according
to low, intermediate, high risk of lung cancer or to a probability estimated by
means of equations developed considering the power of each variable in multiple
regression models (Table 2).
From the radiological point
of view, conventional chest radiographs are the diagnostic tool more often
used. Unfortunately, despite the low radiation doses, chest X-ray (CXR) has low
sensitivity for detection of nodules and a high false-positive rate due to the
summation artifacts, both on standard postero-anterior and lateral projections[8].
Muhm and colleagues reported that almost 90% of peripheral nodules and 75% of
peri-hilar nodules identified during a lung cancer screening program conducetd
through chest computed tomography (CT) were detected after negative CXR
performed within the previous three months[9].
The failure to identify lung
nodules can be due to either an incomplete visual survey by the evaluator[10]
or a nodule’s low conspicuity when located in the upper lung, centrally[11]
or over other body structures such as the clavicle or hilar vessels.
Since its introduction in
1990s, the spiral (CT) became the standard for the detection of focal pulmonary
opacities[12].
The use of CT in chest
imaging initially encountered some reluctance both because CXR was considered
the best radiological technique for its high quality in imaging pulmonary
nodules and also for the air contrast. However, in the late 1970s, CT scan of
lung nodules was proven to be superior to chest radiography and linear
tomography[13].
CT nodule location, size and growth
rate assessment
In the clinical
nomograms, location and size of nodules contribute to the pre-test probability
of malignancy.
Upper and middle lobe
solitary pulmonary nodules have a likelihood ratio for malignancy of 1.2 to
1.6. The upper lobe location has been shown to be an independent predictor of
malignancy[14].
As for size, the majority of
smokers undergoing thin section CT are found to have small lung nodules and the
detection of nodules up to 4 mm in diameter is a routine finding in this
population. The majority of lung nodules smaller than 5 mm are benign, deriving
from scars caused by inflammatory processes, and the prevalence rate of
malignancy in this group is 0-1%, with the exception of one small retrospective
study[15] that reported 2 nodules smaller than 5 mm in diameter as
malignant[16]. However, small size alone it is not enough to exclude
lung cancer: in a study by Ginsberg and colleagues[17], whose
purpose was to determine the etiology of pulmonary nodules resected at
video-assisted thoracoscopic surgery (VATS), 15% of malignant nodules were less
than 1 cm in diameter and approximately 42% were less than 2 cm in diameter. Clinical
context is also very important: a review by Mc Williams and colleagues[18]
on the risk of malignancy in small non-calcified nodules detected by CT
reported a frequency of small pulmonary nodules of 5 to 60% and both a diameter
greater than 10 mm or persisting growth in two surveys CT scan were identified
as predictors of malignancy. In the same review, a smoking history of more than
30 pack-years was associated with an incidence of nodules of about 36-50 % on
CT base, whereas a history of 10 pack-years was associated with nodule
frequency of 23%.
According to Fleishner Society,
the risk of malignancy is 0-1% for nodules <5 mm, 6-28% for nodules 5-10 mm,
33-60% for those >11-20 mm, 64-82% for those >20 mm. Therefore, in an
approach solely based on size and clinical risk of cancer, follow-up CT scans
to assess growth rate in incidentally detected nodules can be required (Table
2)[19]. Since 15% of solid nodules smaller than 1 cm of diameter
contain malignant areas, and this percentage becomes higher with the increase
in diameter, a CT scan repeated after six weeks in order to evaluate the growth
of nodules or its resolution after antibiotic therapy can be a valuable tool[14,20].
The statement by Fleischner
Society derives from different studies: in the Mayo Clinic lung cancer
screening trial non-calcified pulmonary nodules were found in 69% of patients
aged 50 years with a smoking history of 20 pack-years or more (high risk
patients)[21]; in this trial 1.4% of nodules were lung cancers. A
second retrospective review, referred as Benjamin trial, reported that 11% of
examined nodules were malignant.
The measurement of the
doubling time, defined as the time needed for a diameter increase of about 26%,
is probably the most important method for the characterization of small lung
nodules. Generally, a stability of nodule’s size for two years is considered as
a criterion of benignity, thus it doesn’t require further evaluation[22].
Doubling time of malignant nodules is usually between 20 and 300 days (most of
them have a doubling time of less than 100 days)[23,24], while
benign nodules can have a doubling time significantly longer or very short
(less than 30 days). A volume doubling time greater than 400 days is usually
associated with benign lesions such as hamartomas and granulomas[25].
These rules, although consistent, have been questioned in the case of malignant
ground glass opacities that show longer volume doubling times than solid
nodules. Nowadays a new method has been introduced for the lung nodule
assessment and the early detection of lung cancer in individuals with solitary
pulmonary nodules, this is the plasma microRNA biomarkers detection[26].
A high sensitivity and specificity have been shown from this method.
CT nodule pattern
Lung masses
associated with lymphadenopathy, synchronous parenchymal lesions or signs of
mediastinal or chest wall infiltration are malignant until otherwise proven. When
the lung nodule does not show definite benign characteristics such as pop-corn
calcification, intranodular fat, a feeding artery or central vein (typical for
arteriovenous malformations), CT morphologic aspects including CT density,
shape and margins, presence of calcifications or cavities must be taken into
account to establish its probable nature and aetiology. The NELSON (Dutch
Belgian Randomised Lung Cancer Screening) study retrospectively evaluated the
doubling time in solid indeterminate non-calcified nodules, proving that the
size growth was related to morphology, margins, location and size. The study
population included subjects with nodules between 5 and 10 mm in diameter
evaluated at 3 months and 1 year. The results revealed that smooth nodules with
round shape and low CT attenuation did not become malignant, while a volume
increase larger than 130 mm3 of the non-smooth unattached nodules
was the predictor for malignancy[27,28].
As for the density, dense
lesions with a solid appearance are less frequently malignant than ground-glass
opacities[16,13]. About 34% of non-solid nodules represent
carcinomas and the risk of malignancy increases together with the increase in
size.
Small (≤10 mm) ground glass nodules usually represent
adenocarcinoma in situ or atypical adenomatous hyperplasia while adenocarcinoma
is rare. The frequency of invasive adenocarcinoma is greater for pure ground
glass nodules measuring >10 mm, reported varying from 10% to 50%. A ground
glass appearance has also been described for bronchoalveolar cell carcinoma. Nevertheless
one small study reported the resolution of subsolid nodules at follow-up CT
scans when they show larger sizes, a lobular border, a polygonal shape and
partly solid attenuation[29].
Nodule’s margins can be
smooth, lobulated, irregular or spiculated. Defined margins are often sign of
benignity; however, Siegelman and colleagues[30] reported that up to
21% of malignant nodular lesions are characterised by smooth and regular
margins. Malignant nodules generally have irregular and spiculated margins or
lobular border. In the Dutch-Belgian randomized lung cancer screening trial
(Nederlands Leuvens Longkanker Screeningsonderzoek), it has been proved that
nodules with lobular border have a higher likelihood for malignancy compared
with smooth nodules, and that malignant lesions are usually intra-parenchymal,
without attachment to vessels[27,32]. Nodules surrounded by a
ground-glass halo are nonspecific. The halo is often suggestive of infection
(often fungal) or hemorrhage caused by vasculitis or metastatic disease.
As for calcifications, Ko et
al[33] demonstrated that calcifications in malignant lesions are
usually stippled and eccentric. Metastatic nodules often show multiple
calcifications.
Both benign and malignant
lung nodules can have cavitation and air bronchograms. Cavitation can be
suggestive of infection, vasculitis, primary lung cancer, and metastatic
disease. The cavity wall thickness can be regarded as a differential feature
between benign and malignant nodules. A cavitation inside a nodule is found in
lesions more than 3 cm in diameter or in lesions with a diameter≤1 cm. A cavity wall thinner than 4 mm is suggestive of a
benign lesions in 95% of cases, while a wall cavity≤16 mm is usually associated to malignant lesions in a
percentage between 84% and 95%[34]. On CT, Honda et al[35]
reported that an irregular inner cavity wall was significantly more frequent in
malignant compared with benign cavities (49% and 26%, respectively). A linear
outer cavity wall was significantly more common in benign compared with
malignant cavities (32% and 13%, respectively). A notch outer wall was
identified more often in malignant than in benign cavities (54% and 29%,
respectively).
A dilated bronchus leading
into the nodule, the presence of a intranodular bronchiologram, and vascular
convergence suggesting vascular and lymphatic invasion have been also
associated to malignancy.
Clinical Management
Management
strategies for a pulmonary nodule may be complex and final decision often takes
into account multiple variables such as the availability of functional PET
Imaging, local expertise in biopsy techniques, comorbidities, and patient
preference.
Functional Imaging
The enhancement
method in MDCT technique may be a valuable tool since the enhancement up to 15
Humsfeld units suggests a benign aetiology, with a sensitivity and specificity
of 98% and 58% respectively[36]. However, this technique does not
differentiate malignant from infective/inflammatory lesions.
The positron emission
tomography (PET) with 18F-fluorodeoxyglucose (FDG) has been proven to be
accurate in differentiate benign from malignant lesions when used to evaluate a
solitary nodule[37]. According to different studies, PET sensitivity
has been reported in the range of 80%-100%, with a specificity between
40%-100%. A retrospective analysis including 17 studies from Wahidi et al[17]
reported a sensitivity of 87% and a specificity of 83%.
Abnormal 18F-FDG
accumulation can be seen in case of infectious nodules due to fungi and
mycobacteria, sarcoidosis, rheumatoid nodules, and other causes of inflammatory
lung disease, causing false positive results.
Generally, lesions with low
FDG uptake are considered benign, although these lesions should be followed
radiologically because of the elevated number of false negative results[38].
The diagnostic value of PET decreases considerably for lesions measuring less
than 6 mm, while it is usually reserved for lesion measuring 10 mm or more. The
assessment of nodules large 8 to 10 mm in diameter is often associated a large
number of false negatives.
False negative results can
also be due to the low metabolic activity of some tumors such as the
lepidic-predominant adenocarcinomas when minimally invasive or in situ,
mucinous adenocarcinomas and carcinoid tumors.
PET has lower specificity in
distinguishing different forms of benign nodules. The differential diagnosis
must be made among several possibilities including infections, congenital and
neoplastic diseases. Integration with multidetector-tomography evaluating the
shape and the wall thickness of the lesion is mandatory. Furthermore, this
technique must be reserved for those lesions measuring 10 mm or more.
For ground glass opacities
or partly solid nodules, PET Imaging is believed not to be reliable. A
sensitivity between 80-100% and a specificity of 40-100% have been reported for
a threshold uptake value of >1.2[39].
The 99Technetium
methoxyisobutylisonitrile (99TC-MIBI) scintigraphy was also used in one series
to indentify benign chest nodules and differentiate those from malign lesions. Lung
cancer was diagnosed in 50% of patients with malignant lung nodule major than
2.6 cm. Among benign lesions, 76% were negative on 99TC-MIBI scan[40].
Biopsy Techniques
Sampling is
performed on nodules with high probability of malignancy, such as those with
larger size or aggressive features. Sampling methods include transthoracic
needle aspiration and biopsy (TTNAB), transbronchial needle aspiration and
biopsy (TBNA), and minimally invasive video-assisted surgical methods.
The ideal nodules for a
percutaneous sampling approach are those accessible without crossing major
vascular structures[41,42]. Sensitivity varies from 72% to 99%, but
90% is accepted as the average yield. Unfortunately, the determination of
benign disease is often challenging due to the small amount of tissue collected
through this method. The most common complication associated with TTNAB is
pneumothorax, which occurs in 20% to 30% of cases, followed by haemorrhage
(about 1%). The risk factors for pneumothorax include age (between 60 and 69
years), smoking, chronic obstructive pulmonary disease, small size, deeper
location, the need to traverse fissures[43], the number of needle
punctures[44]. False negative results are in a range of 10-30%.
TBNA enables biopsy of
lesions centrally located and involving the airways. The sensitivity of this
technique is widely variable, but has been reported to be 40% to 70% for
nodules in the range of 2-3 cm. Recent advances in ultrathin bronchoscopy,
electromagnetic navigation, and endobronchial ultrasound are promising
technologies but are not yet widely available. The risk of pneumothorax has
been reported in the range of 2-4%. False negative results are in a range of
30-70%.
Among surgical approaches,
open surgery or video-assisted thoracoscopic surgery (VATS) are available. Tamura
et al[45] explore the role of thoracoscopy performed in
FDG-PET negative nodules greater than 15 mm and with distance to pleura<10
mm. The surgical resection was undertaken after the lack of success of less
invasive procedures such as transbronchial biopsy and CT-guided transthoracic
needle aspiration biopsy.
In the trial of Rocco et
al[41], a single-access video-assisted thoracoscopic approach
was used for peripheral pulmonary nodules in an ambulatory setting.
VATS is a safe alternative
to thoracotomy. It is associated with fewer complications but is limited by the
visual determination of the location of the nodule. If the nodule is not close
to the pleural space, the nodule may not be accessible.
Drugs that affect lung nodule evolution
In a randomized
double-blind trial, inhaled budesonide was used to evaluate whether the drug
was able to reduce in number and size persistent CT-detected lung nodules in
high risk asymptomatic subjects. Selected asymptomatic former smokers with lung
nodules underwent treatment with budesonide 800 mg twice daily for 12 months[46].
Budesonide was found to reduce the size of lung nodules in the longest diameter
of 6% of cases while stable disease was observed in 84% of cases.
According to these results,
we can assume that those nodules were probably of inflammatory origin caused by
oxidants and reactive aldehydes. Moreover, recent evidence in literature
suggest a possible anti-carcinogenic properties for molecules such as
budesonide, isothiocyanate and N-acetylcysteine administered orally in an
animal model[47]. Animals previously exposed to cigarette smoke have
been shown to present a higher incidence of both benign and malignant lung
tumors. The administration of the above-mentioned agents, above all budesonide,
was effective in protecting mice from carcinogenicity and preventing tumour
progression.
In this line of evidence,
some other drugs, such as fluticasone have been proved to be effective in
nodule lung regression[48]. In fact in a randomized trial from
subjects recruited having bronchial dysplasia and heavy smoking habit, those
with evidence of lung nodules undertook placebo or fluticasone. The fluticasone
arm showed a decrease in lung nodules number.
DISCUSSION
The management of a
patient with a single lung nodule starts from an accurate evaluation of both
clinical and radiological features. Border, shape, location and the pattern of
calcification are essential features but patient age, smoking history and
history of malignancies must be also taken into account. A close liaison
between the radiologists, interventional radiologists, and clinicians is
mandatory.
A “watch and wait” approach
seems appropriate for those nodules stable over time. It has been suggested
that a nodule stable for at least 2 years is a reliable indicator of benignity,
as well as a 20 days volume doubling time. Nodules larger than 7 mm can be
managed through non-invasive and invasive characterization. An early detection
of lung nodules together with smoking cessation give the patient more
probability to prevent lung cancer. A half of long-term smokers are estimated
to die due to tobacco dependence, which is a disease specified in the 10th
revision of International Classification of Diseases.
Lung cancer screening has
largely improved after the introduction worldwide of CT scanners capable of
imaging the entire chest within a single breath hold. Nodules greater than 7 mm
and less than 3 cm are amenable to nodule enhancement study.
Lung nodules have to be
monitored by CT scan and in some cases by PET, with a frequency depending on
shape, density, size, presence or not of calcifications.
MRI has a limited role
because of limited spatial resolution. PET has been proven to have a
sensitivity of 96% and specificity of 88% for the diagnosis of nodule. However,
the negative predictive value and sensitivity are lowered by its decreased
spatial resolution.
Linear or sheet-like lung
opacities are unlikely to represent lung neoplasms. However non-calcified solid
pulmonary nodules have to be closely monitored until proved to be stable over a
period of two years. Patients with at least 30 pack-year smoking histories have
to be screened and followed up. The frequency of nodule detection increases
proportionally with the narrowing of the slices.
Almost all nodules 4 mm or
smaller are benign. Any calcification usually favours a benign cause. The upper
lobe location increases the likelihood of malignancy. Comorbidities and smoking
habit affect the malignant behaviour of small nodules.
One of these comorbidities
is silicosis which is associated with lung cancer. Profusion of pneumoconiotic
nodules is a risk factor for lung cancer development and likely to evolve in
lung cancer varies in different series[49]. The invasive approach is
indicated for nodule larger than 8 mm in risk patients with higher probability
of malignancy. The trans-thoracic needle aspiration is indicated for
percutaneous sampling without crossing major vascular structures. TBNA enables
biopsy of lesions centrally located with yields of 19% and 62% reported[50,51].
The accuracy of CT guided biopsy is lower in nodules smaller than 10 mm in diameter.
Some prevention therapies are considered potentially capable of reducing lung
nodule in size. The glucocorticoids are effective in reducing lung nodule size
and number, and in preventing lung tumor development; in fact the effectiveness
of budesonide and fluticasone to reduce the size of the nodules suggests an
inflammatory origin of these lesions.
Nevertheless, smoking
cessation program is the most effective therapy in reducing cancer incidence
and malignant transformation of nodules. In a review by Hecht and co-workers we
can see that since we know that gas phase and particulate phase of cigarette
smoke are co-carcinogens and inflammation is closely associated with tumor
promotion, many antioxidants and anti-inflammatory agents have shown efficacy
against lung carcinogenesis in animal models. For example anti COX2 agents may
work in this direction, since this molecule is constitutively expressed as
tumors progress. Therefore sulindac and aspirin are effective chemopreventive
agents in tobacco nitrosamines-treated mice[52].
CONCLUSIONS
In the clinical
approach to a lung nodule, the pretest probability of malignancy, which is
related to patient risk and nodule characteristics can be used to guide
management.
The possible nature of
nodule should be investigated for a therapeutic approach .The patient’s
occupational history should be assessed. Alternatives to CT follow-up include
CT nodule enhancement, FDG-PET, transthoracic or bronchoscopic needle biopsy,
and surgical resection.
Management requires
collaboration of a range of specialists including the clinician, diagnostic and
interventional radiologists, the bronchoscopist, surgeon, and pathologist.
The use of inhaled steroid drugs, along with the smoking
cessation, could be useful to decrease the size of nodules of inflammatory
origin.
CONFLICT
OF INTERESTS
There are no
conflicts of interest with regard to the present study.
REFERENCES
1 Hansell DM,
Bankier AA, MacMahon H, McLoud TC, Müller NL, Remy J. Fleischner Society:
glossary of terms for thoracic imaging. Radiology 2008; 246(3):
697–722
2 Ost D, Fein AM, Feinsilver
SH. Clinical practice: the solitary pulmonary nodule. N Engl J Med 2003;
348: 2535–2542
3 Arakawa H, Shida H, Saito Y,
Johkoh T, Tomiyama N, Tsubamoto M, Honma K. Pulmonary malignancy in silicosis:
factors associated with radiographic detection. Europ J of Radiology
2009: 69: 80-86
4 Bobba R, Holly SJ, Loy T,
Perry MC. Scar Carcinoma of the lung: a historical perspective. Clinical
Lung cancer 2011;12 (3):148-54
5 Robert J Mason, V Courtney
Broaddus, Thomas Martin, Talmadge King Jr., Dean Schraufnagel, John F. Murray,
Jay A. Nadel. Murray and Nadel’s Textbook of Respiratory Medicine. 5th edition
published by Elsevier, 2010
6 Charalambous S, Churhyard GJ,
Murray J, De Cock KM, Corbett EL. Persistent radiological changes following
military tuberculosis in miners exposed to silica dust. Int J Tuberc Lung
Dis 2001; 5(11): 1044-1050
7 Jeremy J. Erasmus, H. Page
McAdams, John E. Connolly. Solitary Pulmonary Nodules: Part II. Evaluation of
the Indeterminate Nodule 1. Radiographics, 2000.
8 Gould MK, Simkovich SM,
Mestaz PJ, Mestaz, MS, Jamie Daniel, Gillian D. Sanders, Gerard Silvestri. Predicting
the probability of malignancy in patients with pulmonary nodules: comparison of
clinical judgment with two validated models. Am J Respir Crit Care Med
2012; 185: A4425
9 Austin JH, Romney BM,
Goldsmith LS. Missed bronchogenic carcinoma: radiographic findings in 27
patients with a potentially resectable lesion evident in retrospect. Radiology
1992; 182(1): 115–122
10 Muhm JR, Miller WE, Fontana RS,
Sanderson DR, Uhlenhopp MA. Lung cancer detected during a screening program
using four-month chest radiographs. Radiology 1983; 148(3):
609–615
11 Samuel S, Kundel HL, Nodine CF,
Toto LC. Mechanism of satisfaction of search: eye position recordings in the
reading of chest radiographs. Radiology 1995; 194(3): 895–902
12 McWilliams A, Mayo J. Computed
tomography-detected noncalcified pulmonary nodules: a review of evidence for
significance and management. Proc Am Thorac Soc 2008; 5: 900-904
13 Schaner EG, Chang AE, Doppman JL,
Conkle DM, Flye MW, Rosenberg SA. Comparison of computed and conventional whole
lung tomography in detecting pulmonary nodules: a prospective
radiologic–pathologic study. AJR 1978; 131: 51–54
14 Takashima S, Sone S, Li F, Maruyama
Y, Hasegawa M, Matsushita T, Takayama F, Kadoya M. Small solitary pulmonary
nodules (< or = 1 cm) detected at population-based CT screening for lung
cancer: reliable high-resolution CT features of benign lesions. Am J Roentgenol
2003; 180: 955-964
15 Midtrun DE, Swensen SJ, Jett JR.
Approach the solitary pulmonary nodule. Mayo Clinic Proc 1993; 68:
378-85
16 Suzuki K, Nagai K, Yoshida J,
Ohmatsu H, Takahashi K, Nishimura M, Nishiwaki Y. Video-assisted thoracoscopic
surgery for small indeterminate pulmonary nodules: indications for preoperative
marking. Chest 1999; 115(2): 563–568
17 Wahidi MM, Govert JA, Goudar RK,
Gould MK, McCrory DC; American College of Chest Physicians. Evidence for the
treatment of patients with pulmonary nodules: when is it lung cancer? ACCP
evidence based clinical practice guidelines (2nd edition). Chest 2007; 132(Suppl
3): 94S–107S
18 Ginsberg
MS, Griff SK, Go BD, Yoo HH, Schwartz LH, Panicek DM. Pulmonary nodules
resected at video-assisted thoracoscopic surgery: etiology in 426 patients. Radiology
1999; 213(1): 277–282
19 Mc Williams A, Mayo J. Computed
tomography-detected noncalcified pulmonary nodules. Proc Am Thorac Soc
2008; 5: 900-904
20 MacMahon H, Austin JH, Gamsu G,
Herold CJ, Jett JR, Naidich DP, Patz EF Jr, Swensen SJ; Fleischner Society.
Guidelines for management of small pulmonary nodules detected on CT scans: a
statement from The Fleishner Society. Radiology 2005; 237:
395-400
21 Libby DM, Smith JP, Altorki NK,
Pasmantier MW, Yankelevitz D, Henschke CI. Managing the small pulmonary nodule
discovered by CT. Chest
2004; 125: 1522-1529
22 Swensen
SJ, Silverstein MD, Ilstrup DM, Schleck CD, Edell ES. The probability of
malignancy in solitary pulmonary nodules: application to small radiologically
indeterminate nodules. Arch Intern Med 1997; 157: 849-855
23 Yankelevitz DF, Henschke CI. Does
2-year stability imply that pulmonary nodules are benign? Am J Roentgenol
1997; 168: 325-328
24 Weiss W. Tumor doubling time and
survival of men with bronchogenic carcinoma. Chest 1974; 65: 3-8
25 Friberg S, Mattson S. On the growth
rates of human malignant tumors: implications for medical decision making. J
Surg Oncol 1997; 65: 284-297
26 Jun S, Ziling L, Nevins WT, Howard
Z, Jipei L, Lei Y, Maria AG, Ruiyun L, Ling C, Min Z, Feng J. Diagnosis of lung
cancer in individuals with solitary pulmonary nodules by plasma microRNA
biomarkers. BMC Cancer 2011; 11: 374
27 Xu DM, van Klaveren RJ, de Bock GH,
Leusveld A, Zhao Y, Wang Y, Vliegenthart R, de Koning HJ, Scholten ET,
Verschakelen J, Prokop M, Oudkerk M. Limited value of shape, margin and CT
density in the discrimination between benign and malignant screen detected
solid pulmonary nodules of the NELSON trial. Eur J Radiol 2008; 68:
347–352
28 Esmaili A, Munden R, Mohammed TLH.
Small Pulmonary nodule management.A survey of the members of the society of
thoracic radiology with comparison to the Fleishner Society Guidelines. J
Thorac Imaging 2011; 26(1): 27-31
29 Felix L, Serra-Tosio G, Lantuejoul
S, Timsit JF, Moro-Sibilot D, Brambilla C, Ferretti GR. Timsit JF. CT
characteristics of resolving ground-glass opacities in a lung cancer screening
programme. Eur J Radiol 2011 Mar; 77(3): 410-416
30 Siegelman SS, Khouri NF, Leo FP,
Fishman EK, Braverman RM, Zerhouni EA. Solitary pulmonary nodules: CT
assessment. Radiology 1986; 160: 307-312
31 Shen J, Liu Z, Todd WN, Zhang H,
Liao, JP, Yu L, Guarnera MA, Li RY, Cai L, Zhan M, Feng J. Diagnosis of lung
cancer in individuals with solitary pulmonary nodules by plasma microRNA
biomarkers. BMC Cancer 2011; 11(374): 1-9
32 Xu DM, van der Zaag-Loonen HJ,
Oudkerk M, Wang Y, Vliegenthart R, Scholten ET, Verschakelen J, Prokop M, de
Koning HJ, van Klaveren RJ. Smooth or attached solid indeterminate nodules
detected at baseline CT screening in the NELSON study: cancer risk during 1
year of follow-up. Radiology. 2009; 250: 264–272
33 Ko JP, Naidich DP. Lung nodule
detection and characterization with multislice CT. Radiol Clin N Am 2003;
41: 575-597
34 Woodring JH, Fried AM. Significance
of wall thickness in solitary cavities of the lung: a follow-up study. Am J
Roentgenol 1983; 140: 473-474
35 Honda O, Tsubamoto M, Inoue A,
Johkoh T, Tomiyama N, Hamada S, Mihara N, Sumikawa H, Natsag J, Nakamura H.
Pulmonary cavitary nodules on computed tomography: differentiation of
malignancy and benignancy. J Comput Assist Tomogr. 2007;31:
943–949
36 Henschke CI, Yankelevitz D,
Westcott J, Davis SD, Fleishon H, Gefter WB, McLoud TC, Pugatch RD, Sostman HD,
Tocino I, White CS, Bode FR, Swensen SJ. Work-up of the solitary pulmonary
nodule. American College of Radiology. ACR Appropriateness Criteria. Radiology
2000 Jun; 215 Suppl: 607-609
37 Gould MK, Maclean CC, Kuschner WG,
Rydzak CE, Owens DK. Accuracy of positron emission tomography for diagnosis of
pulmonary nodule and mass lesions: a meta-analysis. JAMA 2001; 285:
914-924
38 Erasmus JJ, McAdams HP, Patz EF Jr,
Coleman RE, Ahuja V, Goodman PC. Evaluation of primary pulmonary carcinoid
tumors using FDG PET. AJR Am J Roentgenol 1998; 170(5): 1369–1373
39 Chun EJ, Lee HJ, Kang WJ, Kim KG,
Goo JM, Park CM, Lee CH. Differentiation between malignancy and inflammation in
pulmonary ground-glass nodules: The feasibility of integrated (18)F-FDG PET/CT.
Lung Cancer. 2009 Aug; 65(2): 180-186
40 Nikoletic K, Lucic S, Peter A,
Kolarov V, Zeravica R, Srbovan D. Lung 99m TC-MIBI scintigraphy: impact on
diagnosis of solitary pulmonary nodule. Bosnian J of Basic Medic Sciences
2011; 11(3): 174-179
41 Rocco G, Romano V, Accardo R,
Tempesta A, La Manna C, La Rocca A, Martucci N, D’ Aiuto M, Polimeno E. Awake
single access video-assisted thoracoscopic surgery for peripheral pulmonary
nodules in a complete ambulatoyi setting. Ann Thorac Surg 2010; 89:
1625-1628
42 Yankelevitz DF, Vazquez M, Henscke
CI. Special techniques in transthoracic needle biopsy of pulmonary nodules. Radiol
Clin North Am 2000; 38:
267-279
43 Rizzo S, Preda L, Raimondi S,
Meroni S, Belmonte M, Monfardini L, Veronesi G, Bellomi M. Risk factors for
complications of CT-guided lung biopsies. Radiol Med 2011 Jun; 116(4):
548-563
44 Ayyappan AP1, Souza CA, Seely J,
Peterson R, Dennie C, Matzinger F. Ultrathin fine-needle aspiration biopsy of
the lung with transfissural approach: does it increase the risk of
pneumothorax? AJR Am J Roentgenol
2008 Dec; 191(6): 1725-1729
45 Tamura M,
Oda M, Fujimori H, et al. Institutional report-Thoracic Oncologic. Interactive
Cardiovasc and Thoracic Surg 2010, 11: 590-593
46 Veronesi G, Szabo E, Decensi A,
Guerrieri-Gonzaga A, Bellomi M, Radice D, Ferretti S, Pelosi G, Lazzeroni M,
Serrano D, Lippman SM, Spaggiari L, Nardi-Pantoli A, Harari S, Varricchio C,
Bonanni B. Randomized phase II trial of inhaled budesonide versus placebo in
high-risk individuals with CT screen-detected lung nodules. Cancer Prev Res
2011; 4 (1): 34-42
47 Balansky R1, Ganchev G, Iltcheva M,
Steele VE, De Flora S. Prevention of cigarette smoke-induced lung tumors in
mice by budesonide, phenethyl isothiocyanate, and N-acetylcysteine. Int J
Cancer 2010; 126: 1047-1054
48 van den Berg RM1, Teertstra HJ, van
Zandwijk N, van Tinteren H, Visser C, Pasic A, Sutedja TG, Baas P, Golding RP,
Postmus PE, Smit EF. CT detected indeterminate pulmonary nodules in a
chemoprevention trial of fluticasone. Lung Cancer 2008; 60: 57-61
49 Arakawa H1, Shida H, Saito Y,
Johkoh T, Tomiyama N, Tsubamoto M, Honma K. Pulmonary malignancy in silicosis:
factors associated with radiographic detection. Eur J Radiol 2009; 69:
80-86
50 Makris D1, Scherpereel A, Leroy S,
Bouchindhomme B, Faivre JB, Remy J, Ramon P, Marquette CH. Electromagnetic
navigation diagnostic bronchoscopy for small peripheral lung lesions. Eur
Respir J 2007; 29: 1187-1192
51 Gould MK, Donington J, Lynch WR, Mazzone
PJ, Midthun DE, Naidich DP, Wiener RS. Evaluation of individuals with pulmonary
nodules: when is it lung cancer? Chest 2013; 143(5) suppl:
e93S-e120S
52 Hecht S, Kassie F, Hatsukami D.
Chemoprevention of lung carcinogenesis in addicted smokers and ex-smokers. Nature
Rev Cancer 2009; 9: 476-487
Peer reviewers: Nobuhiro Kanaji, MD, PhD,
Department of Internal Medicine, Division of Endocrinology and Metabolism,
Hematology, Rheumatology and Respiratory Medicine, Faculty of Medicine, Kagawa
University, 1750-1, Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan;
Chun-Ru Chien, Department of Radiation Oncology, China Medical University, 2nd
Yuh-Der Rd, North District, 40402, Taiwan.
Refbacks
- There are currently no refbacks.